The long-term goal of this project is the chromosomal mapping and characterization of mutations causing four skeletal dysplasias: nail-patella syndrome (NPS), Langer-Giedeon syndrome (LGS), Ellis van-Creveld syndrome (EvC), and cartilage-hair hypoplasia (CHH). The skeletal dysplasias are a diverse group of over 100 clinical disorders whose underlying biochemical causes are, for the most part, unknown. Delineation of the genes responsible for these varied phenotypes will undoubtedly provide insight into the mechan- isms of normal chondrogenesis and growth. This project will focus on four conditions which are particularly amenable to new approaches for human genomic analysis. The approach to all four conditions will be similar: (1) establish a chromosomal localization by traditional genetic linkage analysis, homozygosity mapping, or identification of gross chromosomal deletions (2) use of yeast artificial chromosome (YAC) cloning and pulsed field gel electrophoresis technology to define DNA fragments closer to, and eventually encroaching upon, the actual mutant locus and (3) establish by sequence analysis the specific mutation causing the disorder. The first step in this process has already been accomplished for NPS and LGS, both of which have known chromosomal locations. NPS is an autosomal dominant condition localized to human chromosome 9q34 and closely linked to the adenylate kinase and ABO blood group loci. LGS, which may be a """"""""contiguous gene syndrome"""""""" involving loci for both multiple exostoses and trichorhinopharyngeal syndrome type 1, has been localized to 8q24 on the basis of patients with microscopically detectable deletions involving this band. EvC and CHH are autosomal recessive skeletal dysplasias whose biochemical bases are unknown. Both are unprecedentedly prevalent in the Old Order Amish. This fact in combination with the structure of the Amish """"""""founder populations"""""""" mean that these disorders are well-suited to the use of """"""""homozygosity mapping"""""""" as well as the traditional genetic linkage approach. Restriction fragment length polymorphisms associated with candidate genes encoding known structural proteins of the cartilage matrix and with anonymous DNA fragments spanning the human genome will be used. Fifty-five nuclear families with EvC, and 72 families with CHH be available for these studies.
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