ISOLATION OF DISEASE GENES FROM CHROMOSOME 5

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DESCRIPTION: The goals of this application are to clone and analyze the genes for diastrophic dysplasia (DTD) and Treacher Collins syndrome (TCOF1). Both of these genes have been localized to narrow regions of human chromosome 5. The applicants have selected these disease genes because they are located in regions of chromosome 5 for which they have already developed significant mapping tools (radiation hybrid panels and YAC and cosmid contigs). DTD is a very rare autosomal recessive disorder characterized by chondrodysplasia (including short stature and joint dysplasia). However, this condition is more common in Finland (0.8 percent), and the gene has been localized in Finnish families to a 60 kb interval surrounding the gene CSF1R. This region is cloned in YACs, and the applicants propose to develop a cosmid contig across the region, identify the coding regions by exon trapping and cDNA capture, and screen these sequences for mutations specific to DTD. A limited amount of material from a DTD family of Estonian background is available for analysis. TCOF1 is an autosomal dominant disorder. The TCOF1 gene is not as well mapped as DTD, but has now been reduced to a 450 kb interval (from 900 kb at the time of the previous application). The applicants propose to develop additional genetic markers from this region to narrow the localization of TCOF1, and to construct a cosmid contig of this reduced region. Since TCOF1 is an autosomal dominant disorder, the applicants will isolate the chromosome 5's from affected individuals in somatic cell hybrids to facilitate sequencing of candidate genes (by avoiding the need for heterozygote detection). Otherwise, the strategy for the isolation of TCOF1 is very similar to that described for DTD.