Original Article
Novel WASP mutation in a patient with Wiskott–Aldrich syndrome: Case report and review of the literature
M. Eghbalia, M. Sadeghi-Shabestarib, F. Najmi Varzanehc,d, A. Zare Bidokic, N. Rezaeia,c,d,
Corresponding author
a Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
b Division of Pediatric Immunology and Allergy, Children's Hospital, Tabriz University Medical Sciences, Tabriz, Iran
c Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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"apellidos" => "Eghbali" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Sadeghi-Shabestari" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "F." "apellidos" => "Najmi Varzaneh" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 3 => array:3 [ "nombre" => "A." "apellidos" => "Zare Bidoki" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:4 [ "nombre" => "N." "apellidos" => "Rezaei" "email" => array:1 [ 0 => "rezaei_nima@tums.ac.ir" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Division of Pediatric Immunology and Allergy, Children's Hospital, Tabriz University Medical Sciences, Tabriz, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 350 "Ancho" => 2425 "Tamanyo" => 57577 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Schematic illustration of the WASP gene with 12 exons and five major functional domains. The mutation; insertion of nucleotide (G) in exon 10 in PRR.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder characterised by eczema, thrombocytopenia with small platelets, recurrent infections and high risk for autoimmunity and malignancy.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1,2</span></a> In WAS patients, thrombocytopenia is an exclusive health concern which is not usually found in other immunodeficiency disorders.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Although malignancy of the reticuloendothelial system and autoimmune disorders such as vasculitis and autoimmune haemolytic anaemia have been associated to WAS,<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">3,4</span></a> the most important causes of death in WAS patients has been attributed to infections, bleeding or malignancy.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">5,6</span></a> A functional deficit of WAS gene mutation is also associated with reduced number and function of T lymphocytes and B lymphocytes and natural killer cell dysfunction.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Early diagnosis of WAS is an important factor in a better prognosis and management in treatment.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Since haematopoietic stem cell transplantation (HSCT) has become the mainstay of treatment for the Wiskott–Aldrich syndrome (WAS), its severe complication including GVHD and infection diseases has restricted HSCT.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a> Some recent studies have revealed HSC gene therapy as a potential treatment in WAS patients.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9,10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In this regard, Moratto et al. who analysed long-term outcome of HSCT in WAS patients have revealed an overall survival of 84.0% for those who received HSCT.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a> Abina et al. also supported the feasibility of HSCT in WAS patients recently.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">A previous study has shown lentiviral gene therapy as a promising treatment for WAS when matched donors are unavailable.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">WAS is a mutation in a gene known as WASP, located on the short arm of the X chromosome (Xp11.4-p11.21) which consists of 12 exons and encodes 502 amino acids.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">14–16</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">WASP is expressed solely in all haematopoietic cell-linages and has five functional domains linked to actin polymerisation and intracellular signal transduction. Abnormal or absent WASP protein caused defective platelet formation as well as dysfunctions in innate, humoral and cellular immunity.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17,18</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">At least 300 unique mutations have been identified in the WASP gene, through all 12 exons. WASP mutations consist of missense and nonsense, insertions, deletions, splice site mutations and complex mutations.<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">19,20</span></a> The missense mutations, as the most common mutations in patients with WAS, are located in the first four exons in WIP-binding domain.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">21</span></a> Usually, splice site mutations are described in introns 6–10; while deletions and insertions are reported through the whole WASP gene.<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">19,20,22</span></a> Gain of function mutations in GTPase-binding domain (GBD) of WASP caused X-linked congenital neutropenia,<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> while loss of function mutations leads to WAS and X-linked thrombocytopenia (XLT).<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">20,24,25</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Despite various mutation in WASP gene among WAS patients, data regarding relationship of phenotype and genotype is sparse. A previous study which examined the genotype correlation with phenotype in 24 WAS patients has revealed a missense mutations in both WAS phenotype in both milder form and severe disease.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In this study, we described an Iranian boy with WAS phenotype with a novel WASP mutation.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Case report</span><p id="par0060" class="elsevierStylePara elsevierViewall">A nine-month old boy was referred to our centre with severe eczema since two months after birth. At four months of age, the patient had streaks of blood covering faeces. He had some minor epistaxis but did not have any heavy bleeding. The patient was suffering from petechia and purpura in his trunk and extremities as a result of thrombocytopenia. The patient did not have any history of recurrent infections including recurrent diarrhoea, rhinitis, sinusitis or pneumonia. He was from non-consanguineous parents. He had six healthy maternal aunts, but his only maternal uncle died at childhood. At the time of referral, the white blood cell count was 8230 (10<span class="elsevierStyleSup">3</span>/μl); haemoglobin 10.5 (g/dl) and platelets (Plt) 23,000(/μl). The differential showed 49.2% lymphocytes and 21.7% neutrophils. The serum levels of immunoglobulins for IgG, IgA, IgM and IgE were 1161<span class="elsevierStyleHsp" style=""></span>mg/dL, 121<span class="elsevierStyleHsp" style=""></span>mg/dL, 97<span class="elsevierStyleHsp" style=""></span>mg/dL, and 2<span class="elsevierStyleHsp" style=""></span>IU/mL, respectively. Repeated CBCs were also compatible with severe thrombocytopenia (20,000/μl and 10,000/μl). Since the patient had thrombocytopenia with small platelets and mild, transient eczema without infections received a score of 2 in Zhu score.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The clinical diagnosis of WAS was made for the patient. By the sequence analysis of all exons, a novel insertion mutation, c.1000-1001insG (N335X), reported that led to a stop codon at amino acid 335 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient is candidate for Allogeneic HSCT from his brother.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">Wiskott–Aldrich syndrome is a rare immune system disorder caused by mutation in a gene on the short arm of chromosome X, which was termed Wiskott–Aldrich syndrome protein gene (WASP).<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a> The <span class="elsevierStyleItalic">WASP</span> gene codes instructions for making a protein called WASP which is 502 amino acid long and is mainly expressed in haematopoietic cells. WASP is involved in activating actin polymerisation by binding to the Arp2/3 complex.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a> In T-cells, Wasp activation via T-cell receptor signalling pathways allows actin cytoskeleton interaction which is responsible for immunological synapse.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Lack of functional WASP signalling impairs the function of the actin cytoskeleton in developing blood cells.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a> White blood cells that lack WASP have less ability to respond to their foreign invaders and form immune synapses causing many of the immune problems related to Wiskott–Aldrich syndrome. Furthermore, loss of functional WASP in platelets disrupts their development, leading to reduced size and early cell death.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">WASP contains several domains, including an Enabled (Ena) and vasodilator-stimulated phosphoprotein (VASP) family, also referred to as a WASP homology domain 1 (WH1), a short basic region (BR), GTPase-binding domain (GBD), a proline-rich region with SH3 binding motifs in N-terminal WASP protein. The C-terminal protein of WASP contains a VCA region, a G-actin-binding verprolin homology (V) domain, a cofilin homology (C) domain and a C-terminal acidic (A) segment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The central acidic region is involved in activating the actin-related protein (Arp)2/3 complex that lead to reorganisation of the actin cytoskeleton.<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">32,33</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">In inactive WASP, an auto inhibited conformation, the verpoline/acidic regions interacts with the GTPase-binding domain. Activation of WASP carries out by binding of Cdc42 to the GBD domain, phosphorylation of WASP-interacting protein (WIP), and binding of SH3 domains containing proteins (such as Nck) to the proline-rich region. The active form of WASP causes actin polymerisation. The N-terminal region of WASP interacts with WIP, binding to the EVH1 domain and stabilising WASP.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> The WIP/WASP complex is disrupted by phosphorylation of WIP that is allowed to activate WASP by Cdc42.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The detection of mutation of WASP was performed by direct sequence analysis of all exons. In this study, we report a unique case of WAS with a novel mutation, insertion of nucleotide (G) in exon 10 (c.1000-1001 ins G), which led to a frameshift (p.G334GfsX1), resulting in a premature termination codon at amino acid 335 (N335X) in the PRR (proline-rich region) of WASP (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><p id="par0095" class="elsevierStylePara elsevierViewall">A proline-rich region in exon 10 has been shown to be necessary for efficient employment of WASP to the immunological synapse in T cells and was required for optimal actin polymerisation activity.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a> This sequence presents binding sites for SH3-domain containing proteins that include the adaptor proteins P47nck and several protein tyrosine kinases including Btk which directly activate WASP through tyrosine phosphorylation.<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">37–39</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">As mentioned above, multiple SH3 domains of Nck are required for activation of WASP.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Therefore, truncated WASP protein with defective in PRR caused inactive protein. Furthermore, in this mutation due to lack of VCA region, the shortened WASP cannot relate with Arp2/3 complex, and lead to disrupt actin polymerisation.</p><p id="par0110" class="elsevierStylePara elsevierViewall">A previous study has described dual mutation in the same gene area (exon 10) in a patient with WAS. One mutation was a one-base insertion and the other was a one-base deletion (G−) which led to frame shift.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The absence of protein or truncated protein is typically related to severe clinical affected patients. However, insertion of nucleotide (G) in exon 10 reduces a few part of WASP after the GBD domain and leaves N-terminal of WASP. So it would be presumed that the truncated WASP can combine with WIP because a WH1 domain still remains intact for WIP binding. Therefore, truncated WASP can be relatively stable and protects from destroying.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In summary, we report a novel mutation N335X or p.G334GfsX1 of the WASP gene in a boy with classic WAS. The mutation resulted in a truncated WASP with manifesting of clinical WAS.</p><p id="par0125" class="elsevierStylePara elsevierViewall">The sequence analysis of genomic DNA coding of the WASP suggests diagnostic detections in patients with WAS and in carrier detection and prenatal diagnosis and also offer expanding the spectrum of WASP mutations for Wiskott–Aldrich syndrome. Other methods such as protein expression analysis of WASP for diagnosis of new mutations should always be attached with direct mutation analysis to compare variation in phenotypes of affected patients. Therefore the western blot method can be done in future approaches.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Authors contributions</span><p id="par0180" class="elsevierStylePara elsevierViewall">All authors have been contributed significantly to the work, have read the manuscript, attest to the validity and agree to its submission.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human subjects and animals in research</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of the patients and/or subjects mentioned in the text.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Funding Source</span><p id="par0175" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres729358" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method and result" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec733410" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 5 => array:2 [ "identificador" => "sec0095" "titulo" => "Authors contributions" ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Protection of human subjects and animals in research" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Right to privacy and informed consent" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Funding Source" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-09-25" "fechaAceptado" => "2015-11-16" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec733410" "palabras" => array:5 [ 0 => "Eczema" 1 => "Recurrent infection" 2 => "Thrombocytopenia" 3 => "Novel mutation" 4 => "Wiskott–Aldrich syndrome" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder, caused by mutations in the WAS protein (WASP) gene and characterised by thrombocytopenia, small platelets, eczema, and recurrent infections associated with increased risk of autoimmunity and malignancy disorders. The gene for WAS has been mapped to the short arm of the X chromosome at Xp 11.22-23 and early detection of patients and diagnosis of new mutation might reduce related complications and increase their life expectancy.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Method and result</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We found a novel mutation by sequence analysis of genomic DNA coding of a 9-month old boy suffering from WAS. The mutation was insertion G in exon 10 of WASP gene. The consequence of the G insertion is a premature stop immediately at amino acid 335 (N335X or p.G334GfsX1) and truncated protein.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusion</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The mutation analysis is helpful for the diagnosis of WAS patients and also expanding the spectrum of <span class="elsevierStyleItalic">WASP</span> mutations for carrier detection and prenatal diagnosis.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method and result" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1248 "Ancho" => 2250 "Tamanyo" => 176753 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Diagrams of <span class="elsevierStyleItalic">WASP</span> mutation identified by sequencing method in patient. (A) Normal. (B) The mutation, 1000–1001 ins (G), which lead to a frameshift (p.G334GfsX1), resulting in a premature termination codon at amino acid 335 (N335X).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 350 "Ancho" => 2425 "Tamanyo" => 57577 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Schematic illustration of the WASP gene with 12 exons and five major functional domains. The mutation; insertion of nucleotide (G) in exon 10 in PRR.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A multiinstitutional survey of the Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K.E. Sullivan" 1 => "C.A. Mullen" 2 => "R.M. Blaese" 3 => "J.A. Winkelstein" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1994" "volumen" => "125" "paginaInicial" => "876" "paginaFinal" => "885" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7996359" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0210" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.D. Ochs" 1 => "A.J. Thrasher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2006.02.005" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2006" "volumen" => "117" "paginaInicial" => "725" "paginaFinal" => "738" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16630926" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0215" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmunity in Wiskott–Aldrich syndrome: an unsolved enigma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Catucci" 1 => "M.C. Castiello" 2 => "F. Pala" 3 => "M. Bosticardo" 4 => "A. Villa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2012.00209" "Revista" => array:5 [ "tituloSerie" => "Front Immunol" "fecha" => "2012" "volumen" => "3" "paginaInicial" => "209" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22826711" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0220" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diffuse large B cell lymphoma in Wiskott–Aldrich syndrome: a case report and review of literature" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Senapati" 1 => "A.J. Devasia" 2 => "S. David" 3 => "M.T. Manipadam" 4 => "S. Nair" 5 => "G.R. Jayandharan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12288-013-0297-5" "Revista" => array:7 [ "tituloSerie" => "Indian J Hematol Blood Transfus" "fecha" => "2014" "volumen" => "30" "numero" => "Suppl. 1" "paginaInicial" => "309" "paginaFinal" => "313" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25435733" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0225" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Wiskott–Aldrich syndrome in the United States and Canada (1892–1979)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.S. Perry 3rd." 1 => "B.D. Spector" 2 => "L.M. Schuman" 3 => "J.S. Mandel" 4 => "V.E. Anderson" 5 => "R.B. McHugh" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1980" "volumen" => "97" "paginaInicial" => "72" "paginaFinal" => "78" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7381651" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0230" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Overexpression of WAVE3 promotes tumor invasiveness and confers an unfavorable prognosis in human hepatocellular carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Ji" 1 => "B. Li" 2 => "Z. Zhu" 3 => "X. Guo" 4 => "W. He" 5 => "Z. Fan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.biopha.2014.11.001" "Revista" => array:6 [ "tituloSerie" => "Biomed. Pharmacother" "fecha" => "2015" "volumen" => "69" "paginaInicial" => "409" "paginaFinal" => "415" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25661390" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0235" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent advances in understanding the pathophysiology of Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Bosticardo" 1 => "F. Marangoni" 2 => "A. Aiuti" 3 => "A. Villa" 4 => "M. Grazia Roncarolo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2008-12-115253" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2009" "volumen" => "113" "paginaInicial" => "6288" "paginaFinal" => "6295" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19351959" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0240" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term outcome following hematopoietic stem-cell transplantation in Wiskott–Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Ozsahin" 1 => "M. Cavazzana-Calvo" 2 => "L.D. Notarangelo" 3 => "A. Schulz" 4 => "A.J. Thrasher" 5 => "E. Mazzolari" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2007-03-076679" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2008" "volumen" => "111" "paginaInicial" => "439" "paginaFinal" => "445" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17901250" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0245" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gene therapy for Wiskott–Aldrich syndrome – long-term efficacy and genotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.J. Braun" 1 => "K. Boztug" 2 => "A. Paruzynski" 3 => "M. Witzel" 4 => "A. Schwarzer" 5 => "M. Rothe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/scitranslmed.3007280" "Revista" => array:5 [ "tituloSerie" => "Sci Transl Med" "fecha" => "2014" "volumen" => "6" "paginaInicial" => "227ra33" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24622513" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0250" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gene therapy for Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Bosticardo" 1 => "F. Ferrua" 2 => "M. Cavazzana" 3 => "A. Aiuti" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Gene Ther" "fecha" => "2014" "volumen" => "14" "paginaInicial" => "413" "paginaFinal" => "421" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25245089" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0255" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott–Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980–2009: an international collaborative study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Moratto" 1 => "S. Giliani" 2 => "C. Bonfim" 3 => "E. Mazzolari" 4 => "A. Fischer" 5 => "H.D. Ochs" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2010-11-319376" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2011" "volumen" => "118" "paginaInicial" => "1675" "paginaFinal" => "1684" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21659547" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0260" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Outcomes following gene therapy in patients with severe Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Hacein-Bey Abina" 1 => "H.B. Gaspar" 2 => "J. Blondeau" 3 => "L. Caccavelli" 4 => "S. Charrier" 5 => "K. Buckland" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/jama.2015.3253" "Revista" => array:6 [ "tituloSerie" => "JAMA" "fecha" => "2015" "volumen" => "313" "paginaInicial" => "1550" "paginaFinal" => "1563" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25898053" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0265" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Aiuti" 1 => "L. Biasco" 2 => "S. Scaramuzza" 3 => "F. Ferrua" 4 => "M.P. Cicalese" 5 => "C. Baricordi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1233151" "Revista" => array:5 [ "tituloSerie" => "Science" "fecha" => "2013" "volumen" => "341" "paginaInicial" => "1233151" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23845947" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0270" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hereditary X-linked thrombocytopenia maps to the same chromosomal region as the Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Donner" 1 => "M. Schwartz" 2 => "K.U. Carlsson" 3 => "L. Holmberg" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "1988" "volumen" => "72" "paginaInicial" => "1849" "paginaFinal" => "1853" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2904289" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0275" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "X-linked thrombocytopenia and Wiskott–Aldrich syndrome are allelic diseases with mutations in the WASP gene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Villa" 1 => "L. Notarangelo" 2 => "P. Macchi" 3 => "E. Mantuano" 4 => "G. Cavagni" 5 => "D. Brugnoni" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng0495-414" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "1995" "volumen" => "9" "paginaInicial" => "414" "paginaFinal" => "417" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7795648" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0280" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Isolation of a novel gene mutated in Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.M. Derry" 1 => "H.D. Ochs" 2 => "U. Francke" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cell" "fecha" => "1994" "volumen" => "79" "paginaInicial" => "922" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0285" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structure and function of the Wiskott–Aldrich syndrome protein" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.D. Ochs" 1 => "L.D. Notarangelo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Opin Hematol" "fecha" => "2005" "volumen" => "12" "paginaInicial" => "284" "paginaFinal" => "291" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15928485" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0290" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wiskott–Aldrich syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G. Bouma" 1 => "S.O. Burns" 2 => "A.J. Thrasher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.imbio.2009.06.009" "Revista" => array:7 [ "tituloSerie" => "Immunobiology" "fecha" => "2009" "volumen" => "214" "paginaInicial" => "778" "paginaFinal" => "790" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19628299" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673602110786" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0295" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical course of patients with WASP gene mutations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Imai" 1 => "T. Morio" 2 => "Y. Zhu" 3 => "Y. Jin" 4 => "S. Itoh" 5 => "M. Kajiwara" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2003-05-1480" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2004" "volumen" => "103" "paginaInicial" => "456" "paginaFinal" => "464" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12969986" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0300" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the Wiskott–Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Jin" 1 => "C. Mazza" 2 => "J.R. Christie" 3 => "S. Giliani" 4 => "M. Fiorini" 5 => "P. Mella" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2003-05-1592" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2004" "volumen" => "104" "paginaInicial" => "4010" "paginaFinal" => "4019" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15284122" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0305" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A peptide derived from the Wiskott–Aldrich syndrome (WAS) protein-interacting protein (WIP) restores WAS protein level and actin cytoskeleton reorganization in lymphocytes from patients with WAS mutations that disrupt WIP binding" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.J. Massaad" 1 => "N. Ramesh" 2 => "S. Le Bras" 3 => "S. Giliani" 4 => "L.D. Notarangelo" 5 => "W. Al-Herz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2011.01.057" "Revista" => array:4 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2011" "volumen" => "127" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21377717" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0310" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the Wiskott–Aldrich syndrome protein affect protein expression and dictate the clinical phenotypes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "H.D. Ochs" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12026-008-8084-3" "Revista" => array:6 [ "tituloSerie" => "Immunol Res" "fecha" => "2009" "volumen" => "44" "paginaInicial" => "84" "paginaFinal" => "88" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19082760" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0315" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Devriendt" 1 => "A.S. Kim" 2 => "G. Mathijs" 3 => "S.G. Frints" 4 => "M. Schwartz" 5 => "J.J. Van Den Oord" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/85886" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "2001" "volumen" => "27" "paginaInicial" => "313" "paginaFinal" => "317" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11242115" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0320" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of WASP mutations in patients with Wiskott–Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Kolluri" 1 => "A. Shehabeldin" 2 => "M. Peacocke" 3 => "A.-M. Lamhonwah" 4 => "K. Teichert-Kuliszewska" 5 => "S.M. Weissman" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1995" "volumen" => "4" "paginaInicial" => "1119" "paginaFinal" => "1126" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8528198" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673609600532" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0325" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "WASP gene mutations in Wiskott–Aldrich syndrome and X-linked thrombocytopenia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Derry" 1 => "J.A. Kerns" 2 => "K.I. Weinberg" 3 => "H.D. Ochs" 4 => "V. Volpini" 5 => "X. Estivill" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1995" "volumen" => "4" "paginaInicial" => "1127" "paginaFinal" => "1135" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8528199" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0330" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of WASP mutations: mutation hotspots and genotype–phenotype disparities in 24 patients with the Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "W.L. Greer" 1 => "A. Shehabeldin" 2 => "J. Schulman" 3 => "A. Junker" 4 => "K.A. Siminovitch" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hum Genet" "fecha" => "1996" "volumen" => "98" "paginaInicial" => "685" "paginaFinal" => "690" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8931701" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0335" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears: eczematoid dermatitis and bloody diarrhea" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.A. Aldrich" 1 => "A.G. Steinberg" 2 => "D.C. Campbell" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3171/2013.10.PEDS12573" "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "1954" "volumen" => "13" "paginaInicial" => "133" "paginaFinal" => "139" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24286157" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0340" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inherited platelet disorders: thrombocytopenias and thrombocytopathies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "G. D’Andrea" 1 => "M. Chetta" 2 => "M. Margaglione" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2450/2009.0078-08" "Revista" => array:6 [ "tituloSerie" => "Blood Transfus" "fecha" => "2009" "volumen" => "7" "paginaInicial" => "278" "paginaFinal" => "292" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20011639" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0345" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "T cell antigen receptor activation and actin cytoskeleton remodeling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Kumari" 1 => "S. Curado" 2 => "V. Mayya" 3 => "M.L. Dustin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbamem.2013.05.004" "Revista" => array:6 [ "tituloSerie" => "Biochim Biophys Acta" "fecha" => "2014" "volumen" => "1838" "paginaInicial" => "546" "paginaFinal" => "556" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23680625" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0350" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Wiskott–Aldrich syndrome: the actin cytoskeleton and immune cell function" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.P. Blundell" 1 => "A. Worth" 2 => "G. Bouma" 3 => "A.J. Thrasher" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3233/DMA-2010-0735" "Revista" => array:6 [ "tituloSerie" => "Dis Markers" "fecha" => "2010" "volumen" => "29" "paginaInicial" => "157" "paginaFinal" => "175" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21178275" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0355" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sex-linked hereditary thrombocytopenia as a variant of Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.L. Canales" 1 => "A.M. Mauer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM196710262771703" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1967" "volumen" => "277" "paginaInicial" => "899" "paginaFinal" => "901" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4168739" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0360" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Scar1 and the related Wiskott–Aldrich syndrome protein: WASP, regulate the actin cytoskeleton through the Arp2/3 complex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L.M. Machesky" 1 => "R.H. Insall" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Biol" "fecha" => "1998" "volumen" => "8" "paginaInicial" => "1347" "paginaFinal" => "1356" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9889097" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0365" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Haploinsufficiency of protamine-1 or-2 causes infertility in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Cho" 1 => "W.D. Willis" 2 => "E.H. Goulding" 3 => "H. Jung-Ha" 4 => "Y.C. Choi" 5 => "N.B. Hecht" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/88313" "Revista" => array:7 [ "tituloSerie" => "Nat Genet" "fecha" => "2001" "volumen" => "28" "paginaInicial" => "82" "paginaFinal" => "86" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11326282" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S073510970501171X" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0370" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Miguel" 1 => "Y. Sasahara" 2 => "M. Calamito" 3 => "I.M. Antón" 4 => "A. Elkhal" 5 => "M.D. Gallego" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.0610275104" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci" "fecha" => "2007" "volumen" => "104" "paginaInicial" => "926" "paginaFinal" => "931" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17213309" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0375" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott–Aldrich syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "B.F. Volkman" 1 => "K.E. Prehoda" 2 => "J.A. Scott" 3 => "F.C. Peterson" 4 => "W.A. Lim" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cell" "fecha" => "2002" "volumen" => "111" "paginaInicial" => "565" "paginaFinal" => "576" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12437929" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0380" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Wiskott–Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Badour" 1 => "J. Zhang" 2 => "F. Shi" 3 => "M.K. McGavin" 4 => "V. Rampersad" 5 => "L.A. Hardy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Immunity" "fecha" => "2003" "volumen" => "18" "paginaInicial" => "141" "paginaFinal" => "154" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12530983" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0385" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wiskott–Aldrich syndrome protein physically associates with Nck through Src homology 3 domains" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "O.M. Rivero-Lezcano" 1 => "A. Marcilla" 2 => "J.H. Sameshima" 3 => "K.C. Robbins" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Mol Cell Biol" "fecha" => "1995" "volumen" => "15" "paginaInicial" => "5725" "paginaFinal" => "5731" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7565724" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0390" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence that the Wiskott–Aldrich syndrome protein may be involved in lymphoid cell signaling pathways" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Cory" 1 => "L. MacCarthy-Morrogh" 2 => "S. Banin" 3 => "I. Gout" 4 => "P.M. Brickell" 5 => "R.J. Levinsky" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "1996" "volumen" => "157" "paginaInicial" => "3791" "paginaFinal" => "3795" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8892607" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0395" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nck and phosphatidylinositol 4,5-bisphosphate synergistically activate actin polymerization through the N-WASP-Arp2/3 pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Rohatgi" 1 => "P. Nollau" 2 => "H.Y. Ho" 3 => "M.W. Kirschner" 4 => "B.J. Mayer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.M103856200" "Revista" => array:7 [ "tituloSerie" => "J Biol Chem" "fecha" => "2001" "volumen" => "276" "paginaInicial" => "26448" "paginaFinal" => "26452" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11340081" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109709034718" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0400" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A case of Wiskott–Aldrich syndrome with dual mutations in exon 10 of the WASP gene: an additional de novo one-base insertion, which restores frame shift due to an inherent one-base deletion, detected in the major population of the patient's peripheral blood lymphocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "T. Ariga" 1 => "M. Yamada" 2 => "Y. Sakiyama" 3 => "O. Tatsuzawa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "1998" "volumen" => "92" "paginaInicial" => "699" "paginaFinal" => "701" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9657775" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000004400000005/v1_201609110107/S0301054616000057/v1_201609110107/en/main.assets" "Apartado" => array:4 [ "identificador" => "5554" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000004400000005/v1_201609110107/S0301054616000057/v1_201609110107/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054616000057?idApp=UINPBA00004N" ]
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| 2021 February | 13 | 9 | 22 |
| 2021 January | 7 | 5 | 12 |
| 2020 December | 2 | 0 | 2 |
| 2020 October | 1 | 0 | 1 |
| 2020 July | 0 | 1 | 1 |
| 2018 March | 2 | 0 | 2 |
| 2018 February | 5 | 3 | 8 |
| 2018 January | 6 | 5 | 11 |
| 2017 December | 10 | 2 | 12 |
| 2017 November | 5 | 4 | 9 |
| 2017 October | 14 | 7 | 21 |
| 2017 September | 4 | 7 | 11 |
| 2017 August | 10 | 4 | 14 |
| 2017 July | 15 | 4 | 19 |
| 2017 January | 2 | 0 | 2 |
| 2016 September | 3 | 1 | 4 |
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