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RAPID COMMUNICATION
Molecular characterization of the complement C1q, C2 and C4 genes in Brazilian patients with juvenile systemic lupus erythematosus
Bernadete L LiphausI,
Corresponding author
bernadete.liphaus@hc.fm.usp.br

corresponding author
, Natalia UmetsuI, Adriana A JesusII, Silvia Y BandoI, Clovis A SilvaII,III, Magda Carneiro-SampaioI
I Faculdade de Medicina da Universidade de São Paulo, Instituto da Criança, Laboratório de Investigação Médica 36, São Paulo/SP, Brazil
II Faculdade de Medicina da Universidade de São Paulo, Instituto da Criança, Unidade de Reumatologia, São Paulo/SP, Brazil
III Faculdade de Medicina da Universidade de São Paulo, Disciplina de Reumatologia, São Paulo/SP, Brazil
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          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Type I C2 deficiency in juvenile systemic lupus erythematosus patients 2 &#40;P2&#41; and 3 &#40;P3&#41;&#46; A &#8211; Nucleotide sequence alignment for P2 and P3&#59; B and C &#8211; Nucleotide chromatograms for P2 and P3&#44; respectively&#46; NG&#95;11730&#46;1 is the reference DNA sequence for C2&#44; and NG&#95;11730 is the codified sequence for C2 &#40;final region of exon 6&#41;&#46; The blue arrow indicates the last nucleotide of exon 6&#44; and the red arrow indicates the initial deletion site&#59; D &#8211; Agarose gel electrophoresis showing the heterozygous 28 bp deletion in exon 6 of the C2 gene&#46; Lane 1&#58; 100 bp DNA ladder&#59; lane 2&#58; P2&#59; lane 3&#58; P3&#59; lane 4&#58; positive control&#59; lane 5&#58; negative control&#46; The blue and red arrows indicate the 174 bp and 146 bp fragments&#44; respectively&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Inherited deficiencies of the complement components C1q&#44; C2 and C4 are frequently associated with the development of systemic lupus erythematosus &#40;SLE&#41; due to the impaired clearance of apoptotic debris&#44; a decreased capacity for immune-complex handling&#44; and&#47;or their role in peripheral B-cell tolerance <a class="elsevierStyleCrossRefs" href="#bib1">1-9</a>&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Homozygous C1q deficiency is the strongest genetic risk factor related to SLE <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#44;&#46; Similarly&#44; both Type I and II C2 deficiency have been associated with SLE <a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;&#46; In addition&#44; homozygous C4A deficiency is approximately 10 times more frequent in patients with SLE <a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Few studies have evaluated the non-coding regions and mRNA expression of complement genes&#46; Furthermore&#44; complement deficiencies are rare among SLE patients but are common among patients with juvenile SLE &#40;JSLE&#41; <a class="elsevierStyleCrossRef" href="#bib23">23</a>&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">We previously showed an underlying primary complement deficiency in seven JSLE patients <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#46; We had access to DNA samples and&#47;or peripheral cells from four of these patients&#44; and to better understand these inherited deficiencies&#44; we conducted a molecular characterization of the C1q&#44; C2 and C4 genes&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><p id="para50" class="elsevierStylePara elsevierViewall">Among 72 JSLE patients&#44; 16 had primary immunodeficiency&#44; and seven of the 16 were determined to have complement deficiency based on a combination of low or undetectable serum levels of C1q&#44; or C1s&#44; C1r&#44; C2&#44; C3 or C4 with normal levels of the other components in at least two samples and low activity&#47;inactive disease &#40;SLEDAI-2K score&#60;4&#41; <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#46; Therefore&#44; we selected four patients&#58; patient 1 &#40;P1&#41; had undetectable serum C1q&#44; normal C3 and C4 levels&#44; negative anti-C1q and available DNA and mononuclear cells&#59; patient 2 &#40;P2&#41; had decreased IgA&#44; C2 and C4 serum levels and stored DNA but no cells available for culture&#59; patient 3 &#40;P3&#41; had decreased C2 and normal C3 and C4 levels&#59; and patient 4 &#40;P4&#41; had repeated decreased C4 and normal C1q&#44; C2 and C3 levels and peripheral cells available for culture &#40;<a class="elsevierStyleCrossRefs" href="#tbl1">Tables 1 and 2</a>&#41;&#46; Three healthy controls matched by age and gender and with normal complement levels were also enrolled&#46; Patients fulfilled the revised American College of Rheumatology classification criteria&#44; and informed consent was obtained for all participants after the local ethics committee had approved the study <a class="elsevierStyleCrossRef" href="#bib24">24</a>&#44;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para60" class="elsevierStylePara elsevierViewall">We previously determined the C4 gene copy number by quantitative real-time polymerase chain reaction &#40;qRT-PCR&#41;&#44; as reported <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#44;<a class="elsevierStyleCrossRef" href="#bib26">26</a> &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41;&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">All exons and 3&#8242; and 5&#8242; non-coding regions &#40;UTR&#41; of the C1q and C2 genes &#40;3 exons each for the C1q A&#44; B&#44; and C chains and 18 exons for the C2 gene&#41; were sequenced&#46; Primers &#40;Supplementary Table&#41; were designed using the reference sequences deposited in GenBank &#40;NG&#95;007282&#46;1 for C1qA&#44; NG&#95;007283&#46;1 for C1qB&#44; NG&#95;007565&#46;1 for C1qC and NG&#95;011730&#46;1 for C2&#41; with the <span class="elsevierStyleItalic">Primer-BLAST</span> program&#46; DNA was obtained using the QIAamp DNA Blood Midi kit &#40;N&#176;51104 Qiagen&#44; Hilden&#44; Germany&#41;&#44; and purity and concentration were determined with a <span class="elsevierStyleItalic">Nanovue</span>&#174; spectrophotometer &#40;GE Healthcare&#44; USA&#41;&#46; Each PCR reaction was performed in a final volume of 25 &#181;l containing 100 ng of DNA&#44; 20 mM Tris-HCl &#40;pH 8&#46;4&#41;&#44; 50 mM KCl&#44; 2&#46;0 mM MgSO4&#44; 100 &#181;M each of dATP&#44; dCTP&#44; dGTP and dTTP&#44; 0&#46;5 &#181;M of each primer and 1&#46;5 U of High-Fidelity Platinum Taq DNA Polymerase &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41;&#46; The amplification conditions included 35 cycles of 95&#176;C for 30 s&#44; 60&#176;C for 30 s and 72&#176;C for 2 min&#44; with an initial denaturing step of 95&#176;C for 5 min and a final extension step of 72&#176;C for 7 min&#46; Products were purified using the GFX PCR DNA and Gel Band Purification Kit &#40;GE Healthcare Life Science&#44; UK&#41;&#46; Amplicons and primers were sent to Centro de Estudos do Genoma Humano for sequencing&#46; The BioEdit and ClustalW sequence alignment editors &#40;http&#58;&#47;&#47;www&#46;mbio&#46;ncsu&#46;edu&#47;bioedit&#47;bioedit&#46;html&#41; were used to align the nucleotide sequences&#46; The BLAST program &#40;http&#58;&#47;&#47;blast&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;Blast&#46;cgi&#41; was used to search variant sequences obtained from the human genomic database&#46; The Chromas software program was used for chromatogram visualization&#46; Type I C2 deficiency was evaluated by PCR as previously described and confirmed by gene sequencing <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#44;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">The quantitative analysis of C1q&#44; C2 and C4 mRNA was performed using peripheral mononuclear cells obtained by centrifugation using Ficoll-Paque Plus &#40;GE Healthcare&#44; Piscataway&#44; NJ&#44; USA&#41; and cultured in supplemented DMEM medium &#40;10&#37; fetal bovine serum&#44; 10&#44;000 U&#47;ml penicillin and 100 g&#47;ml streptomycin&#41; at 37&#176;C with 5&#37; CO<span class="elsevierStyleInf">2</span> for 36 hours&#46; Parallel cultures were stimulated with 100 U&#47;&#181;l of recombinant human interferon gamma &#40;IFN&#947;&#59; N&#176;300-02 Preprotech&#44; Rocky Hill&#44; NJ&#44; USA&#41; as previously described <a class="elsevierStyleCrossRef" href="#bib28">28</a>&#46; RNA was obtained from cultures using an RNeasy Midi Kit &#40;N&#176;74104&#44; Qiagen&#44; Hilden&#44; Germany&#41;&#46; RNA &#40;500 ng&#41; was reverse-transcribed to produce complementary DNA &#40;cDNA&#41; using the <span class="elsevierStyleItalic">SuperScript III First-Strand Synthesis System for RT-PCR</span> &#40;N&#176;18080-051&#44; Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41;&#46; The qRT-PCR was performed using 2 &#181;l of cDNA&#44; 1 &#181;M each of forward and reverse primers and 1X <span class="elsevierStyleItalic">SYBR Green Mix QuantiFast PCR Kit</span> &#40;N&#176;204054&#44; Qiagen&#44; Hilden&#44; Germany&#41; in a StepOnePlus Real-Time PCR System &#40;Applied Biosystems&#44; Forrest City&#44; CA&#44; USA&#41;&#46; The cycling parameters included an initial 15 min hot start at 95&#176;C&#44; followed by 50 cycles of 15 s at 95&#176;C and 30 s at 60&#176;C&#46; C4B primers were designed based on a GenBank reference sequence &#40;NG&#95;011638&#44; Supplementary Table&#41;&#46; Glyceraldehyde 3-phosphate dehydrogenase &#40;GAPDH&#41; was used as an endogenous reference gene for qRT-PCR reaction normalization&#46; Relative expression &#40;RE&#41; was determined by the standard curve method&#44; and mean values are presented here as relative variation expression &#40;RVE&#41; obtained from RVE &#61; target gene RE &#8211; GAPDH RE&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">A t-test was used to compare the control and untreated samples and the patient treated and untreated samples&#46; p&#60;0&#46;05 was considered significant&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">RESULTS</span><p id="para100" class="elsevierStylePara elsevierViewall">C1q gene sequencing &#40;P1&#41; revealed a heterozygous silent mutation in exon 3 of the A chain &#40;c&#46;276 A&#62;G Gly&#41;&#44; a homozygous single-base change in the 3&#8242; UTR of the B chain &#40;c&#42;78 A&#62;G&#41;&#44; and a heterozygous silent mutation in exon 2 of the C chain &#40;c&#46;126 C&#62;T Pro&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figures 1</a>&#44;<a class="elsevierStyleCrossRef" href="#fig2">2</a>&#44;<a class="elsevierStyleCrossRef" href="#fig3">3</a>&#41;&#46; The qRT-PCR analysis revealed that C1qA mRNA expression was decreased compared with that of healthy controls &#40;p&#60;0&#46;05&#41; and was also decreased after IFN&#947; stimulation &#40;treated cells&#41; compared with that of non-treated cells&#59; C1qB mRNA expression was decreased compared with that of controls and did not change with stimulation&#44; and C1qC mRNA expression was increased compared with that of controls and was even higher after IFN&#947; stimulation &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5A</a>&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><elsevierMultimedia ident="fig2"></elsevierMultimedia><elsevierMultimedia ident="fig3"></elsevierMultimedia><elsevierMultimedia ident="fig5"></elsevierMultimedia><p id="para110" class="elsevierStylePara elsevierViewall">P1&#39;s healthy mother had an identical but homozygous silent mutation in the A chain&#44; a homozygous single-base change in the B chain&#44; a heterozygous silent mutation in the C chain&#44; and an additional missense mutation in the A chain &#40;c&#46; 295 A&#62;C Ile-Leu&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#46; The peripheral cells of the mother were not available for mRNA expression&#46;</p><p id="para120" class="elsevierStylePara elsevierViewall">P2 and P3 had a heterozygous 28 bp deletion at exon 6&#44; characterizing Type I C2 deficiency&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig4">Figure 4</a>&#46; The C2 mRNA expression &#40;P3&#41; was 23 times lower compared with that of controls and did not change after IFN&#947; stimulation &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5B</a>&#41;&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia><p id="para130" class="elsevierStylePara elsevierViewall">The C4B mRNA expression in P4 was significantly decreased compared with that of controls and increased after IFN&#947; stimulation &#40;<a class="elsevierStyleCrossRef" href="#fig5">Figure 5C</a>&#41;&#46; The C4A mRNA expression was not technically adequate&#44; and it was therefore not considered for analysis&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">DISCUSSION</span><p id="para140" class="elsevierStylePara elsevierViewall">For the first time in JSLE patients&#44; we showed heterozygous silent mutations&#44; a homozygous single-base change in the 3&#8242; UTR and decreased mRNA expression for the C1q gene&#59; a heterozygous Type I deficiency and decreased mRNA expression for the C2 gene&#59; and decreased mRNA expression for the C4B gene&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">Although complement deficiencies were the first identified genetic risk factors for SLE&#44; it remains unclear how these deficiencies should be assessed <a class="elsevierStyleCrossRef" href="#bib2">2-4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib3">7</a>&#44;<a class="elsevierStyleCrossRef" href="#bib4">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib7">27</a>&#44;&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">Studies have described nonsense and missense mutations in the C1q gene&#44; with a total of 12 causative mutations <a class="elsevierStyleCrossRef" href="#bib3">3-5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib4">10-12</a>&#44;<a class="elsevierStyleCrossRef" href="#bib5">23</a>&#44;&#46; Single nucleotide polymorphisms and silent mutations have also been described <a class="elsevierStyleCrossRef" href="#bib12">12</a>&#44;<a class="elsevierStyleCrossRef" href="#bib38">38</a>&#46; However&#44; although there were no amino acid changes due to the identified base changes&#44; the mRNA expression of the C1qA&#44; B and C chains was altered&#46; There is evidence that silent mutations can influence gene expression via alternative splicing by altering the exonic splicing enhancer or silencer sites <a class="elsevierStyleCrossRef" href="#bib39">39</a>&#46; There is no evidence that heterozygous mutations of the C1q gene can lead to lupus if the other allele is normal&#46; Of note&#44; our patient presented photosensitivity&#44; which is a characteristic associated with a single-nucleotide change in the C1qA gene <a class="elsevierStyleCrossRef" href="#bib38">38</a>&#46; In addition&#44; Rafiq reported allelic variance in the 3&#8242; UTR of the C1qB chain associated with low C1q serum levels <a class="elsevierStyleCrossRef" href="#bib36">36</a>&#46; The fact that the 3&#8242; UTR single-base change in C1qB was homozygous implies that the mother and father each have one allele with the same sequence variants&#46; P1&#39;s mother had normal C1q levels and did not present any symptoms of autoimmune disease&#59; however&#44; she harbored silent mutations with an additional missense mutation in the A chain&#46; Because the C1q protein was present in P1&#39;s mother&#44; it becomes questionable whether the observed variants are&#44; by themselves&#44; pathogenic <a class="elsevierStyleCrossRef" href="#bib40">40</a>&#44;<a class="elsevierStyleCrossRef" href="#bib41">41</a>&#46; Peripheral cells from the patient&#39;s father and mother were not available for mRNA expression analysis&#44; which could have addressed on the latter speculation&#46;</p><p id="para170" class="elsevierStylePara elsevierViewall">An intriguing aspect of these results was the observation of mRNA expression from the C1q chains after IFN&#947; stimulation&#46; IFN&#947; is able to induce and up-regulate complement production by monocytes <a class="elsevierStyleCrossRef" href="#bib28">28</a>&#44;<a class="elsevierStyleCrossRef" href="#bib42">42</a>&#44;<a class="elsevierStyleCrossRef" href="#bib43">43</a>&#46; C1qA and B expression was decreased&#44; and C1qC was increased&#44; which suggests deregulated production that could influence the heterotrimeric assembly of protein&#46; Nanjou et al&#46; demonstrated that only one defect in any C1q chain can compromise the entire synthesis and secretion of the C1q protein <a class="elsevierStyleCrossRef" href="#bib37">37</a>&#46; Because mRNA was still expressed&#44; it is unlikely that the observed base changes could completely block protein expression&#44; and alternative causes must be considered&#46; Therefore&#44; further work assessing mRNA stability and translation efficiency will be needed&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">Type I C2 deficiency is due to a 9 bp deletion from the 3&#8242; end of exon 6 and a 19 bp deletion from the 5&#8242; region of the following intron&#44; leading to a frame shift and a premature stop codon <a class="elsevierStyleCrossRef" href="#bib2">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#44;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#44;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#46; More than half of individuals with primary C2 deficiency develop SLE or lupus-like disease <a class="elsevierStyleCrossRef" href="#bib2">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#46; C2 gene sequencing was performed because most Type I deficiencies associated with SLE are homozygous and because Zhu et al&#46; have reported a compound heterozygous Type I and II C2 deficiency in an African-American family <a class="elsevierStyleCrossRef" href="#bib14">14-16</a>&#44;&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">Although the Type I C2 deficiency was heterozygous&#44; it resulted in a 23-fold reduction in mRNA expression&#46; Lipsker et al&#46; observed decreased but still detectable C2 levels in SLE patients with a heterozygous Type I C2 deficiency <a class="elsevierStyleCrossRef" href="#bib43">43</a>&#46; Our findings raise both &#40;1&#41; the possibility that heterozygous C2 mutations alone or in combination with other factors could lead to SLE and &#40;2&#41; the question of why C2 mRNA expression was so low when the patient still had one functional C2 gene&#46; Therefore&#44; further JSLE patients with decreased C2 serum levels should be evaluated for Type I C2 deficiency to better understand the relationship of this condition with the disease&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">The C4A and C4B genes each have 41 exons and differ from each other by only five nucleotides&#46; The number of gene copies ranges from two to eight&#44; and deficiencies in these two genes have been associated with SLE <a class="elsevierStyleCrossRef" href="#bib18">18-20</a>&#44;<a class="elsevierStyleCrossRef" href="#bib19">44</a>&#44;&#46; P4 had persistently low C4 serum levels&#44; with two copies of C4A and three of C4B&#59; the C4B mRNA expression in this individual was significantly decreased compared with controls and increased after IFN&#947; stimulation&#46; Although this was an interesting finding&#44; attributing the abnormal C4B mRNA expression to a gene mutation requires presuming that there were mutations in most or all of her three copies&#44; which is possible but unlikely&#46; Additionally&#44; we would presume that there was a simultaneous problem with C4A transcription&#44; which could not be evaluated&#46; Thus&#44; further work is needed to clarify the role of decreased C4B mRNA expression in JSLE pathogenesis&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">This study was unprecedented because it involved the sequencing of all exons and non-coding regions of the C1q and C2 genes as well as the evaluation of mRNA expression&#46; The limitations included the small number of patients&#44; which created the need for experimental replicates&#44; and the need for fresh mononuclear cells for mRNA expression analysis&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">In conclusion&#44; silent mutations and single-base changes in the 3&#8242; non-coding region may modulate mRNA transcription and C1q production&#59; Type I C2 deficiency should be evaluated in JSLE patients with decreased C2 serum levels&#59; and further studies are needed to clarify the role of decreased C4B mRNA expression in JSLE pathogenesis&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">AUTHOR CONTRIBUTIONS</span><p id="para230" class="elsevierStylePara elsevierViewall">All authors drafted&#44; critically reviewed for intellectual content and approved the final version of the manuscript&#46; Liphaus BL contributed to study conception and design&#44; data analysis and interpretation and manuscript writing&#46; Umetsu N contributed to data acquisition&#44; analysis and interpretation&#46; Jesus AA contributed to data acquisition&#44; analysis and interpretation&#46; Bando SY contributed to data analysis and interpretation and manuscript writing&#46; Silva CA contributed to patient enrollment and data acquisition&#46; Carneiro-Sampaio M contributed to study conception&#44; data interpretation and manuscript intellectual content&#46;</p></span></span>"
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        0 => array:2 [
          "identificador" => "xpalclavsec1582430"
          "titulo" => "KEYWORDS"
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        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:2 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
        ]
        3 => array:2 [
          "identificador" => "cesec30"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec40"
          "titulo" => "DISCUSSION"
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        5 => array:2 [
          "identificador" => "cesec50"
          "titulo" => "AUTHOR CONTRIBUTIONS"
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        6 => array:2 [
          "identificador" => "xack639329"
          "titulo" => "ACKNOWLEDGMENTS"
        ]
        7 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2014-08-14"
    "fechaAceptado" => "2015-01-05"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1582430"
          "palabras" => array:5 [
            0 => "Juvenile systemic lupus erythematosus"
            1 => "Complement deficiency"
            2 => "C1q&#44; C2 and C4 genes"
            3 => "Silent mutation"
            4 => "Non-coding region"
          ]
        ]
      ]
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    "tieneResumen" => true
    "resumen" => array:1 [
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVE&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">To perform a molecular characterization of the C1q&#44; C2 and C4 genes in patients with juvenile systemic lupus erythematosus&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Patient 1 &#40;P1&#41; had undetectable C1q&#44; patient 2 &#40;P2&#41; and patient 3 &#40;P3&#41; had decreased C2 and patient 4 &#40;P4&#41; had decreased C4 levels&#46; All exons and non-coding regions of the C1q and C2 genes were sequenced&#46; Mononuclear cells were cultured and stimulated with interferon gamma to evaluate C1q&#44; C2 and C4 mRNA expression by quantitative real-time polymerase chain reaction&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">C1q sequencing revealed heterozygous silent mutations in the A &#40;c&#46;276 A&#62;G Gly&#41; and C &#40;c&#46;126 C&#62;T Pro&#41; chains&#44; as well as a homozygous single-base change in the 3&#8242; non-coding region of the B chain &#40;c&#42;78 A&#62;G&#41;&#46; C1qA mRNA expression without interferon was decreased compared with that of healthy controls &#40;p&#60;0&#46;05&#41; and was decreased after stimulation compared with that of non-treated cells&#46; C1qB mRNA expression was decreased compared with that of controls and did not change with stimulation&#46; C1qC mRNA expression was increased compared with that of controls and was even higher after stimulation&#46; P2 and P3 had Type I C2 deficiency &#40;heterozygous 28 bp deletion at exon 6&#41;&#46; The C2 mRNA expression in P3 was 23 times lower compared with that of controls and did not change after stimulation&#46; The C4B mRNA expression of P4 was decreased compared with that of controls and increased after stimulation&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSIONS&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">Silent mutations and single-base changes in the 3&#8242; non-coding regions may modify mRNA transcription and C1q production&#46; Type I C2 deficiency should be evaluated in JSLE patients with decreased C2 serum levels&#46; Further studies are needed to clarify the role of decreased C4B mRNA expression in JSLE pathogenesis&#46;</p></span>"
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            "titulo" => "RESULTS&#58;"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">C1qA gene sequencing from juvenile systemic lupus erythematosus patient 1 &#40;P1&#41; and P1&#39;s mother&#46; A &#8211; Nucleotide sequence alignment for P1 and P1&#39;s mother&#59; B &#8211; Amino acid sequence for P1 and P1&#39;s mother&#59; C and D &#8211; Nucleotide chromatograms of P1 and P1&#39;s mother&#44; respectively&#46; NG&#95;007282&#46;1 is the reference codified sequence for C1qA&#46; The arrows indicate the variation sites &#40;exon 3&#44; c&#46;276 A&#62;G Gly&#59; c&#46;295 A&#62;C Ile-Leu&#41;&#46;</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">C1qB gene sequencing from juvenile systemic lupus erythematosus patient 1 &#40;P1&#41; and P1&#39;s mother&#46; A &#8211; Nucleotide sequence alignment for P1 and P1&#39;s mother&#59; B and C &#8211; Nucleotide chromatograms of P1 and P1&#39;s mother&#44; respectively&#46; NG&#95;007283&#46;1 is the reference codified or mRNA sequence for C1qB&#46; The arrow indicates the variation site &#40;3&#8242; UTR c&#42;78 A&#62;G&#41;&#46;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">C1qC gene sequencing from juvenile systemic lupus erythematosus patient 1 &#40;P1&#41; and P1&#39;s mother&#46; A &#8211; Nucleotide sequence alignment for P1 and P1&#39;s mother&#59; B and C &#8211; Nucleotide chromatograms of P1 and P1&#39;s mother&#44; respectively&#46; NG&#95;007565&#46;1 is the reference codified sequence for C1qC&#46; The arrow indicates the variation site &#40;exon 2&#44; c&#46;126 C&#62;T Pro&#41;&#46;</p>"
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          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Type I C2 deficiency in juvenile systemic lupus erythematosus patients 2 &#40;P2&#41; and 3 &#40;P3&#41;&#46; A &#8211; Nucleotide sequence alignment for P2 and P3&#59; B and C &#8211; Nucleotide chromatograms for P2 and P3&#44; respectively&#46; NG&#95;11730&#46;1 is the reference DNA sequence for C2&#44; and NG&#95;11730 is the codified sequence for C2 &#40;final region of exon 6&#41;&#46; The blue arrow indicates the last nucleotide of exon 6&#44; and the red arrow indicates the initial deletion site&#59; D &#8211; Agarose gel electrophoresis showing the heterozygous 28 bp deletion in exon 6 of the C2 gene&#46; Lane 1&#58; 100 bp DNA ladder&#59; lane 2&#58; P2&#59; lane 3&#58; P3&#59; lane 4&#58; positive control&#59; lane 5&#58; negative control&#46; The blue and red arrows indicate the 174 bp and 146 bp fragments&#44; respectively&#46;</p>"
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          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Relative expression of mRNA in cells from juvenile systemic lupus erythematosus patients and controls and after in vitro IFN-&#947; stimulation &#40;treated&#41;&#46; A &#8211; The relative expression of the C1q A&#44; B and C chains in P1&#39;s cells&#59; B &#8211; The relative expression of C2 in P3&#39;s cells&#59; C &#8211; The relative expression of C4B in P4&#39;s cells&#46; RVE &#8211; relative variation expression&#46; &#42;indicates a significant difference&#44; p&#60;0&#46;05&#46;</p>"
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          "leyenda" => "<p id="tfn1" class="elsevierStyleSimplePara elsevierViewall">&#42;There was neither patient with C1r or C1s alterations&#44; nor with persistent low C3 levels&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col">Patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">C1q &#40;33-209 mg&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">C2 &#40;14-25 mg&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">C3 &#40;0&#46;5-1&#46;8 g&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">C4 &#40;0&#46;1-0&#46;4 g&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">C4 copy number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">P1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top"><span class="elsevierStyleBold">0&#46;0&#47;0&#46;0</span> &#40;anti-C1q -&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">8&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;87&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Not done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">P2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">135&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top"><span class="elsevierStyleBold">4&#46;1&#47;0&#46;0</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top"><span class="elsevierStyleBold">0&#46;0&#47;0&#46;08</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">2 copies C4A 1 copy C4B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">P3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">4&#46;6&#47;12 &#40;anti-C1q &#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top"><span class="elsevierStyleBold">3&#46;4&#47;14</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">Not done&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleBold">P4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">38&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">14&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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          "en" => "<p id="spara60" class="elsevierStyleSimplePara elsevierViewall">-Complement component values from four juvenile systemic lupus erythematosus patients selected for molecular characterization from a cohort of seven patients previously determined to have primary complement deficiencies&#46;</p>"
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                              AA Jesus \n
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        "titulo" => "ACKNOWLEDGMENTS"
        "texto" => "<p id="para240" class="elsevierStylePara elsevierViewall">The authors gratefully acknowledge all of the patients for their kind participation&#46; The authors also acknowledge Luis EC Andrade and Estela M Novak for their assistance with laboratory tests and mRNA expression data analysis&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Financial support&#58;</span> This study was supported by S&#227;o Paulo Research Foundation &#40;FAPESP&#41; grant 2008&#47;58238-4&#46;</p>"
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos