Investigating the molecular basis of Jeune and Cenani-Lenz syndromes
This thesis describes an investigation into the molecular basis of two rare autosomal recessive conditions: Jeune asphyxiating thoracic dystrophy (JATD) and Cenani-Lenz syndrome (CLS). JATD is a skeletal dysplasia sometimes complicated by chronic nephritis, hepatic and pancreatic fibrosis, and retinal degeneration. Although it is a serious condition with a high mortality and morbidity, predominantly from respiratory insufficiency in infancy and chronic renal failure in childhood, its molecular basis is currently unknown. This project focused on twelve consanguineous and nineteen non-consanguineous affected families. Haplotype analysis was undertaken in the consanguineous families to exclude linkage to several previously proposed candidate genes and loci. A homozygosity mapping approach was then adopted, and a genome-wide linkage scan was carried out in the three most statistically powerful consanguineous families. Each family was consistent with linkage to a different locus, on chromosomes 3q24-q26, 8q24 and 14q24-q32. The remaining families were genotyped across each locus to define minimal critical intervals. A number of candidate genes were then selected and screened for mutations in families which were consistent with linkage, but no mutations were identified. CLS is a distal limb malformation characterised by total digit syndactyly and radio ulnar synostosis. Limb deformity (Id) mice have a very similar phenotype. The Id phenotype is caused by mutations in the Formin-1 gene, leading to loss of Gremlin expression in the limb bud mesenchyme. In this project, haplotype analysis in one consanguineous CLS family excluded linkage both to FORMIN-1 (FMN-1) and to GREMLIN, which are immediately adjacent to each other on chromosome 15ql3. Haplotype analysis in another consanguineous CLS family was consistent with linkage to this region, but no mutations were identified in either FMN-1 or GREMLIN. The coding sequence of GREMLIN was analysed in two further consanguineous and three non-consanguineous CLS families, but no mutations were identified.