Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family Journal Article
| Authors: | Niemann, S.; Zhao, C.; Pascu, F.; Stahl, U.; Aulepp, U.; Niswander, L.; Weber, J. L.; Müller, U. |
| Article Title: | Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family |
| Abstract: | Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of ∼8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development. |
| Keywords: | controlled study; human tissue; gene mutation; human cell; mutation; case report; nonhuman; proteins; mouse; animals; mice; gene; gene locus; genetic association; haplotypes; drosophila; embryo development; pedigree; consanguinity; gene mapping; homozygosity; amino terminal sequence; gene identification; nucleotide sequence; genetic disorder; sequence homology; wnt proteins; genetic marker; nonsense mutation; fibroblast growth factors; lethal mutant; genetic linkage; chromosome 17q; null allele; chromosome mapping; sequence analysis, dna; autosomal recessive disorder; limb malformation; chromosomes, human, pair 17; fetus malformation; craniofacial malformation; fibroblast growth factor 10; consanguineous marriage; humans; human; male; female; priority journal; article; drosophila wingless gene; tetra amelia; urogenital tract malformation; wnt3 gene; ectromelia |
| Journal Title: | American Journal of Human Genetics |
| Volume: | 74 |
| Issue: | 3 |
| ISSN: | 0002-9297 |
| Publisher: | Cell Press |
| Date Published: | 2004-03-01 |
| Start Page: | 558 |
| End Page: | 563 |
| Language: | English |
| DOI: | 10.1086/382196 |
| PROVIDER: | scopus |
| PMCID: | PMC1182269 |
| PUBMED: | 14872406 |
| DOI/URL: | |
| Notes: | Am. J. Hum. Genet. -- Cited By (since 1996):118 -- Export Date: 16 June 2014 -- CODEN: AJHGA -- Molecular Sequence Numbers: GENBANK: NM_030753; -- Source: Scopus |
