ISOLATION OF THE PSEUDOACHONDROPLASIA DISEASE GENE

假性软骨发育不全是一种显性遗传性软骨发育不良

Pseudoachondroplasia is a dominantly inherited chondrodysplasia characterized by short limbs, joint laxity, a waddling gait, and early onset osteoarthropathy. Diagnostic radiographic abnormalities of the epiphyses and metaphyses, as well as unique inclusion bodies within chondrocytes define the condition. The principal objective of the proposed work is to understand the molecular basis of pseudoachondroplasia and, through the isolation of the disease gene, determine the biological function of the gene product. We have recently determined that the pseudoachondroplasia phenotype is linked to polymorphic markers in the pericentromeric region of chromosome 19. A form of multiple epiphyseal dysplasia has also been recently mapped to the same chromosomal region. We propose to use the recent data to achieve the following goals: (A) To isolate the gene that is defective in pseudoachondroplasia. We will refine the genetic interval containing the disease gene, isolate molecular clones comprising the region, identify candidate genes, and characterize the disease gene. We will test the hypothesis that the gene of interest encodes an extracellular matrix protein that is expressed in a cartilage-specific manner. (B) To determine if there is genetic heterogeneity within the pseudoachondroplasia/multiple epiphyseal dysplasia disease spectrum. We will carry out linkage studies using the chromosome 19 markers to determine if the disease gene in additional families is linked to the same region. (C) To determine the chromosomal location of the disease gene in a family unlinked to the pseudoachondroplasia region of chromosome 19. Using a single, large family and both candidate gene and genome wide markers, we will identify a second locus within this group of chondrodysplasias. This work will directly benefit families with pseudoachondroplasia and multiple epiphyseal dysplasia in providing earlier and more specific diagnosis, and thereby improved clinical care. The specific features of the expression and function of the gene may also suggest rational approaches to therapy. In addition, because the region of chromosome 19 linked to pseudoachondroplasia does not encode any known components of cartilage, the proposed studies represent the opportunity to define a novel gene product from this tissue and identify the molecular basis of the osteoarthropathy that results from defects in it, opening up a broad new area of biological and biochemical investigation.