covid
Buscar en
Gaceta Médica de Bilbao
Toda la web
Inicio Gaceta Médica de Bilbao Diagnostico molecular del gen HFE de la hemocromatosis hereditaria
Journal Information
Vol. 105. Issue 3.
Pages 85-93 (January 2008)
Share
Share
Download PDF
More article options
Vol. 105. Issue 3.
Pages 85-93 (January 2008)
Full text access
Diagnostico molecular del gen HFE de la hemocromatosis hereditaria
Molecular diagnosis of the haereditary hemochromatosis gen (HFE)
Herentziazko hemokromatosiaren HFE genearen diagnostiko molekularra
Visits
29385
A. San-Miguel
Corresponding author
asanmiguel@hispavista.com

Correspondencia: Dr. A. San Miguel-Hernández. Laboratorio de Análisis Clínicos. Hospital Universitario Rio Hortega., Avda Cardenal Torquemada s/n. 47010. Valladolid. Espa˜a UE.
, N. Alonso, B. Calvo, R. Iglesias, R. San-Miguel, F.J. Martín-Gil
Servicio de Análisis Clínicos. Hospital Universitario Rio Hortega. Valladolid. Espa˜a UE.
This item has received
Article information
Resumen

La hemocromatosis hereditaria (HH) es una enfermedad metabólica resultante de una acumulación excesiva de hierro en la sangre, el hígado, corazón y otros órganos. Está causada por mutaciones en el gen HFE. Las personas con HH llevan casi siempre dos copias de la mutación Cys282Tyr del gen HFE, o una copia de esa mutación y otra de la mutación His63Asp del mismo gen. Las personas con dos copias de la mutación His63Asp y las personas portadoras de una sola copia de cualquiera de las dos mutaciones no tienen un riesgo mayor de sufrir hemocromatosis que la poblacion normal. Una de cada 9 personas es portadora de alguna de estas mutaciones: lleva una copia del gen normal y otra con la mutación. Las personas con la enfermedad han recibido una copia mutante de cada uno de sus dos progenitores que, frecuentemente, son individuos portadores de la mutación que no presentan hemocromatosis.

A pesar de la alta incidencia de esta enfermedad (0,3%), la mayoría de los casos permanecen sin diagnosticar. Afortunadamente, la HH está entre las pocas enfermedades que tienen un tratamiento simple y efectivo si se diagnostica tempranamente. Bajo tratamiento, la esperanza de vida del paciente es normal.

La prueba de ADN permite la detección inequívoca tanto de personas portadoras de una copia de la mutación, con riesgo de tener hijos con la enfermedad, como de personas con dos copias de la mutación que ya presenta la enfermedad o que la desarrollarán con una altísima probabilidad en el futuro.

Los objetivos del diagnostico de HH consisten en el estudio molecular de las mutaciones del gen HFE y en el consejo genético. Se debe realizar consejo genético para informar al paciente y a la familia de la forma de herencia, las implicaciones de la enfermedad, riesgo genético. Se debe realizar la historia familiar, árbol genealógico y los test genéticos para clarificar el estado de los miembros de la familia.

Palabras clave:
Hemocromatosis hereditaria
análisis de mutaciones
Summary

Hereditary hemochromatosis (HH), also known as iron overload disease, is an inherited disorder in which iron accumulates in blood (because too much is absorbed by the intestines), liver, heart, pancreas, pituitary gland, joints and other tissues. HH is most often caused by a faulty gene on chromosome 6 named HFE. Most of affected individuals have two copies of the Cys282Tyr mutation of the HFE gene while only a low percentage of individuals have either one or two copies of the second mutation, which is called His6Asp.The individuals having two copies of His63Asp mutation and those having a only copy of any of both mutations have not more risk for hemochromatosis than that the normal people. One of each 9 people is carrier of some of these mutations: they have a copy of the normal gene and another one of the mutation. The people with the disease have received a mutant copy of each one of their two parents who, frequently, are individual carriers of the mutation which they do not display hemochromatosis. In spite of the high incidence of this disease (0.3%), most of the cases remain without diagnose. Luckily, HH is between the few diseases that with an earlier diagnosis have a simple and effective treatment. Under treatment, the life expectancy of the patient is normal.

The HH DNA test for screening of the general population lead to an unequivocal detection of either the carrying people having a copy of the mutation (with risk of having children with the disease) or the people with two copies of the mutation (those that displays the disease or that will with a highest probability develop it in the future).

Primary objectives in HH diagnosis are: to examine HFE mutations and to increase individual information on genetic risk. Genetic advice should be carried out to the patient and their family on the inheritance form, the implications of the disease and the genetic risk. Genealogical familiar history, genetic tree and genetic test should be realised to clarify the family situation.

Key words:
Hereditary hemochromatosis
mutations analysis
Laburpena

Herentziazko hemokromatosia (HH) odolean, gibelean, bihotzean eta beste organo batzuetan burdin gehiegi metatzetik sortzen den gaixotasun metabolikoa da. HFE genearen mutazioek eragiten dute. HH duten pertsonek HFE genearen Cys282Tyr mutazioaren bi kopia daramatzate ia beti, baita gene beraren His63Asp mutazioren beste bat ere. His63Asp mutazioaren bi kopia dituzten pertsonak eta bi mutazioen zeinahiren kopia bakarra duten pertsona eramaileek ez dute biztanleria normalak baino arrisku handiagoa hemokromatosia sufritzeko. 9 lagun bakoitzetik bat mutazio horietakoren baten eramailea da: gene normalaren kopia bat dute eta beste bat, mutazioduna. Gaixotasuna duten pertsonek guraso bakoitzetik kopia mutante bat jaso dute eta, sarritan, hemokromatosia ez duten mutazioaren eramaileak dira.

Gaixotasun honen intzidentzia handia izan arren (% 0,3), kasu gehienak ez dira diagnostikatzen.

Zorionez, HH goiz diagnostikatuz gero, tratamendu bakun eta eraginkorra duen gaixotasun gutxienetakoen artean dago. Tratamendu pean, gaixoaren bizi-itxaropena normala da.

ADN probak mutazioaren kopia baten eramaileak diren eta gaixotasuna garatuko duten seme-alabak izateko arriskua duten pertsonak huts egin gabe antzematen laguntzen du, baita jadanik gaixotasuna duten mutazioaren bi kopiak dituzten pertsonak edo etorkizunean probabilitate oso handiarekin garatuko dutenak ere. HH diagnostikoaren helburuak HFE genearen mutazioen azterlan molekularrean eta aholku genetikoan oinarritzen dira. Aholku genetikoa egin behar da gaixoari eta familiari herentzia motaren, gaixotasunaren inplikazioen eta arrisku genetikoaren berri emateko. Familiaren historia, zuhaitz genealogikoa eta test genetikoak egin behar dira familiako kideen egoera argitzeko.

Gako-hitzak:
Herentziazko hemokromatosia
mutazioen analisia
Full text is only aviable in PDF
Bibliografia
[1.]
Merryweather-Clarke A.T., Pointon J.J., Shearman J.D..
Global prevalence of putative haemochromatosis gene mutations.
J Med Genet., 34 (1997), pp. 275-278
[2.]
Schettler G., und Greten H..
Innere Medizin Thieme Verlag Stuttgart, 9 (1998), pp. 875-877
[3.]
Feder J.N., Gnirke A., Thomas W..
A novel MHC class 1-like gene is mutated in patients with hereditary haemochromatosis Nat Genet., 13 (1996), pp. 399-408
[4.]
Lebron J.A., Bennett M.J., Vaughn D.E..
Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.
Cell, 93 (1998), pp. 111-123
[5.]
Feder J.N., Penny D.M., Irrinki A..
The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.
Proc Natl Acad Sci USA, 95 (1998), pp. 1472-1477
[6.]
Gottschalk R., Seidl C., Löffler T..
HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic hemochromatosis Tissue Antigens, 51 (1998), pp. 270-275
[7.]
Beutler E., Gelbart T., West C..
Mutation analysis in hereditary hemochromatosis Blood Cells Mol Dis., 22 (1996), pp. 187-194
[8.]
Burt M.J., Geroge P.M., Upton J.D..
The significance of haemochromatosis gene mutations in the general population: implications for screening.
Gut, 43 (1998), pp. 830-836
[9.]
Catherine Mura, Odile Raguenes, Claude Férec HFE.
Mutations Analysis in 711 Hemochromatosis probands: Evidence for S65C Implication in mild form of Hemochromatosis.
Blood, 93 (1999), pp. 2502-2505
[10.]
Bernard P.S., Ajioka R.S., Kushner J.J., Wittwer C.T..
Homogeneous multiplex genotyping of Hemochromatosis mutations with Fluorescent Hybridization Probes.
Am J Pathol., 153 (1998), pp. 1055-1059
[11.]
Carella M., D'Ambrosio L., Totaro A., et al.
Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.
Am J Hum Genet., 60 (1997), pp. 828-832
[12.]
Espinós Pérez D..
Algunos comentarios sobre la hemocromatosis.
Ann Med Intern, 17 (2000), pp. 625-627
[13.]
Kris V Kowdley, Jonathan F tait, Robin L Bennett, Arno G Motulsky; Universiti of Washington. www.geneclinics.org
[14.]
Lyon E., Frank E.L..
Hereditary hemochromatosis since discovery of the HFE gene.
Clin Chem., 4 (2001), pp. 1147-1156
[15.]
Jouanolle A.M., Gandon G., Jezequel P., et al.
Hemochromatosis and HLA-H.
Nature Genet., 14 (1996), pp. 251-252
[16.]
Morrison E.D., Kowdley K.V..
Genetic liver disease in adults. Early recognition of the three most common causes.
Postgrad Med., 107 (2000), pp. 147-152
[17.]
Jazwinska E.C., Pyper W.R., Burt M.J., et al.
Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis.
Am J Hum Genet., 56 (1995), pp. 428-433
[18.]
Sanchez M., Bruguera M., Quintero E., Barrio Y., Mazzara R., Rodes J., Oliva R..
Hereditary hemochromatosis in Spain.
Genet Test, 4 (2000), pp. 171-176
[19.]
Witte D.L., Crosby W.H., Edwards C.Q., Fairbanks V.F., Mitros A.A..
Practice guideline development task force of College of American Pathologists. Hereditary Hemochromatosis.
Clin Chem Acta, 245 (1996), pp. 139-200
[20.]
Hashem B., El-Serag H.G., Inadomi J.M., Kowdley K.V..
Screening for hereditary hemochromatosis in siblings and children of affected patients.
Ann Intern Med., 132 (2000), pp. 261-269
[21.]
Hahn J.U., Steiner M., Bochnig S., Schmidt H., Schuff-Werner P., Kerner W..
Evaluation of a diagnostic algorithm for hereditary hemochromatosis in 3,500 patients with diabetes.
Diabetes Care, 29 (2006), pp. 464-466
[22.]
De Domenico I., Ward D.M., Musci G., Kaplan J..
Iron overload due to mutations in ferroportin.
Haematologica., 91 (2006), pp. 92-95
[23.]
Nisselle A.E., Collins V.R., Gason A.A., Flouris A., Delatycki M.B., Allen K.J., Aitken M.A., Metcalfe S.A..
Educational outcomes of a workplace screening program for genetic susceptibility to hemochromatosis.
Clin Genet., 69 (2006), pp. 163-170
[24.]
Matas M., Guix P., Castro J.A., Parera M., Ramon M.M., Obrador A., Picornell A..
Prevalence of HFE C282Y and H63D in Jewish populations and clinical implications of H63D homozygosity.
Clin Genet., 69 (2006), pp. 155-162
[10:]
Alexander J., Kowdley K.V..
Hereditary hemochromatosis: genetics, pathogenesis, and clinical management.
Ann Hepatol., 4 (2005), pp. 240-247
[25.]
Star A., Tu E., Niemann J., Gabriel J.C., Joiner C.S., Valcke C..
Label-free detection of DNA hybridization using carbon nanotube network field-effect transistors.
Proc Natl Acad Sci U S A, 103 (2006), pp. 921-926
[26.]
Beutler E..
Hemochromatosis: Genetics and Pathophysiology.
Annu Rev Med., 57 (2006), pp. 331-347
[27.]
van der A.D.L., Peeters P.H., Grobbee D.E., Roest M., Voorbij H.A., van der Schouw Y.T..
HFE genotypes and dietary heme iron: No evidence of strong gene-nutrient interaction on serum ferritin concentrations in middle-aged women.
Nutr Metab Cardiovasc Dis., 16 (2006), pp. 60-68
[28.]
von Delius S., Lersch C., Schulte-Frohlinde E., Fend F., Dobritz M., Schmid R.M., Eckel F..
Hepatocellular carcinoma associated with hereditary hemochromatosis occurring in non-cirrhotic liver.
Z Gastroenterol., 44 (2006), pp. 39-42
[29.]
Jones R..
Screening for hereditary hemochromatosis in the primary-care setting.
Nat Clin Pract Gastroenterol Hepatol., 3 (2006), pp. 12-13
[30.]
Nichols L., Dickson G., Phan P.G., Kant J.A..
Iron binding saturation and genotypic testing for hereditary hemochromatosis in patients with liver disease.
Am J Clin Pathol., 125 (2006), pp. 1-5
[31.]
Vazquez-Romero M., Boixeda-de M.i., quel D., Vallcorba-Gomez del Valle I., Foruny-Olcina J.R., Martin de Argila C., San Roman-Cos-Gayon C..
Hereditary hemochromatosis: phenotypic study in a Spanish population.
Med Clin (Barc), 125 (2005), pp. 721-726
[32.]
Fleming R.E., Britton R.S., Waheed A., Sly W.S., Bacon B.R..
Pathophysiology of hereditary hemochromatosis.
Semin Liver Dis., 25 (2005), pp. 411-419
[33.]
Ombiga J., Adams L.A., Tang K., Trinder D., Olynyk J.K..
Screening for HFE and iron overload.
Semin Liver Dis., 25 (2005), pp. 402-410
[34.]
Meeker J.A., Miller S.M..
Hereditary hemochromatosis.
MLO Med Lab Obs., 37 (2005), pp. 14-16
[35.]
Meier P., Schuff-Werner P., Steiner M..
Hemochromatosis gene HFE Cys282Tyr mutation analysis in a cohort of Northeast German hospitalized patients supports assumption of a North to South allele frequency gradient throughout Germany.
Clin Lab, 51 (2005), pp. 539-543
[36.]
Vazquez Romero M., Boixeda de Miquel D., Martin de Argila de Prados C., Vallcorba Gomez del Valle I., Cabello Albendea P., Lopez San Roman A., San Roman Cos-Gayon C..
Familiar penetrancy of HFE gene: four brothers of the same family affected by hereditary haemochromatosis.
Rev Esp Enferm Dig., 97 (2005), pp. 608-609
[37.]
Pietrangelo A., Trautwein C..
Mechanisms of disease: The role of hepcidin in iron homeostasis—implications for hemochromatosis and other disorders.
Nat Clin Pract Gastroenterol Hepatol., 1 (2004), pp. 39-45
[38.]
Zoller H., Cox T.M..
Hemochromatosis: genetic testing and clinical practice.
Clin Gastroenterol Hepatol., 3 (2005), pp. 945-958
[39.]
Pietrangelo A..
Hereditary hemochromatosis - A new look at an old Disease.
New Engl J Med., 350 (2004), pp. 2383-2397
[40.]
Rouault T., Mishra L., Deng C.X..
A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression.
Cell Metab., 2 (2005), pp. 399-409
[41.]
Verga Falzacappa M.V., Muckenthaler M.U..
Hepcidin: iron-hormone and anti-microbial peptide.
[42.]
Le Gac G., Ferec C..
The molecular genetics of haemochromatosis.
Eur J Hum Genet., 13 (2005), pp. 1172-1185
[43.]
Gehrke S.G., Herrmann T., Kulaksiz H., Merle U., Bents K., Kaiser I., Riedel H.D., Stremmel W..
Iron stores modulate hepatic hepcidin expression by an HFE-independent pathway.
Digestion., 72 (2005), pp. 25-32
Copyright © 2008. Academia de Ciencias Médicas de Bilbao
Download PDF
Article options