Brachydactyly type A1 (BDA1) is a congenital disorder that affects normal bone development and patterning. Affected individuals have short fingers, broad hands and are generally short in stature. BDA1 was the first human trait described in terms of autosomal dominant Mendelian inheritance. Missense mutations in the Indian hedgehog (IHH) gene have been shown to be responsible for the disorder, and a second locus has been mapped to a region on chromosome 5p13.3-p13.2 in a single kindred. We have since obtained DNA from four new BDA1-affected kindreds. We were successful in identifying IHH mutations in 3 of these families, thus further supporting a role for IHH in the pathogenesis of BDA1.
We have also obtained DNA from a consanguineous BDA1-affected kindred in which mutations in IHH, as well as linkage to the chromosome 5p13.3-p13.2 region, have been excluded. Taken together, this data supports existence of a third locus for BDA1. A genome-wide linkage screen was initiated in the family, and linkage was observed at a region on chromosome 20q11.22-q11.23. Subsequent screening of the candidate gene GDF5, located in the chromosome 20 disease locus, revealed a homozygous c.1138C>T nucleotide change in all affected members of the sibship. This mutation is hypothesized to disrupt the highly-conserved tertiary structure of the GDF5 monomer which is critical for the dimerization and maturation of GDF5, thus leading to interrupted GDF5 signaling and severe BDA1 pathogenesis in homozygous individuals. This thesis identifies GDF5 as the second disease gene for BDA1, and describes the first case of BDA1 in a consanguineous family.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/27506 |
| Date | January 2007 |
| Creators | Byrnes, Ashley M |
| Publisher | University of Ottawa (Canada) |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 155 p. |
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