Genetic variation in ICF syndrome: Evidence for genetic heterogeneity
| Autor: | Jacques J. M. van Dongen, Bernd H. Belohradsky, Cisca Wijmenga, Dominique Smeets, David Valentine, Peter L. Pearson, Lambert P. van den Heuvel, Erik Björck, Eric Strengman, R. Scott Hansen, Corry M.R. Weemaes, J.A.F.M. Luyten, Giorgio Gimelli, E. Graham Davies |
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| Rok vydání: | 2000 |
| Předmět: |
Breuk-gevoelige plaatsen in chromosomen bij de mens
Genetics (Fragile) breakage-prone sites in human chromosomes Genetic heterogeneity DNMT3B Nonsense mutation Locus (genetics) Biology Compound heterozygosity Molecular biology Immuunstoornissen in relatie tot kinderen met (pre-)maligne aandoeningen embryonic structures Genetic variation Missense mutation Immune deficiencies in children (pre-)malignant diseases Allele human activities Genetics (clinical) |
| Zdroj: | Human Mutation, 16, 509-517 Human Mutation, 16, 6, pp. 509-517 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/1098-1004(200012)16:6<509::aid-humu8>3.0.co;2-v |
| Popis: | ICF syndrome is a rare autosomal recessive immunoglobulin deficiency, sometimes combined with defective cellular immunity. Other features that are frequently observed in ICF syndrome patients include facial dysmorphism, developmental delay, and recurrent infections. The most diagnostic feature of ICF syndrome is the branching of chromosomes 1, 9, and 16 due to pericentromeric instability. Positional candidate cloning recently discovered the de novo DNA methyltransferase 3B (DNMT3B) as the responsible gene by identifying seven different mutations in nine ICF patients. DNMT3B specifically methylates repeat sequences adjacent to the centromeres of chromosome 1, 9, and 16. Our panel of 14 ICF patients was subjected to mutation analysis in the DNMT3B gene. Mutations in DNMT3B were discovered in only nine of our 14 ICF patients. Moreover, two ICF patients from consanguineous families who did not show autozygosity (i.e. homozygosity by descent) for the DNMT3B locus did not reveal DNMT3B mutations, suggesting genetic heterogeneity for this disease. Mutation analysis revealed 11 different mutations, including seven novel ones: eight different missense mutations, two different nonsense mutations, and a splice-site mutation leading to the insertion of three aa’s. The missense mutations occurred in or near the catalytic domain of DNMT3B protein, indicating a possible interference with the normal functioning of the enzyme. However, none of the ICF patients was homozygous for a nonsense allele, suggesting that absence of this enzyme is not compatible with life. Compound heterozygosity for a missense and a nonsense mutation did not seem to correlate with a more severe phenotype. Hum Mutat 16:509–517, 2000. © 2000 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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