The investigator has evaluated a 5 generation family (MN1) with a previously undefined autosomal dominant muscle disease. Although this family has the clinical features associated with myotonic dystrophy (myotonia, neck and facial weakness, frontal balding, cataracts and cardiac arrhythmias), affected individuals do not have the CTG expansion associated with DM, nor is the disease locus linked to the DM region of chromosome 19. The investigator also excluded linkage to the other genetic loci that cause myotonia, i.e., the muscle sodium channel gene (SCN4A) and the chloride channel gene (CLC-1). The identification of a second locus for myotonic dystrophy will facilitate the identification of additional families with the MN1 form of myotonic dystrophy and will be a first step toward identifying the MN1 gene. Because the MN1 disorder causes the same broad range of clinical features as classic myotonic dystrophy, the eventual isolation and characterization of the gene(s) affected will provide insights into the pathology of both DM and the disease afflicting the MN1 family.
Our specific aims are: A) To further characterize patients clinically by performing: 1) blood tests to look for muscle fiber disruption, glucose intolerance, and primary gonadal failure in males; 2) EMG studies to better characterize their myotonia; 3) EKG studies to look for conduction block and arrhythmias; 4) muscle biopsies to characterize their myopathy. B) To identify and study additional branches of the MN1 family that are affected by the disease and to look for additional unrelated families with the MN1 form of myotonic dystrophy. C) To localize the MN1 gene to a specific chromosome by linkage analysis. Preliminary results indicate a high likelihood of detecting linkage by performing a genome screen using a marker spacing of 10 cM (360 markers). D) To construct a high resolution (1-2 cM) genetic map for the chromosomal region containing the MN1 gene. In order to genetically narrow the critical region containing the MN1 gene to a 1-2 cM interval it is anticipated that we will need to identify additional branches of the family and or other families with the MN1 form of """"""""myotonic dystrophy"""""""". Once the MN1 locus has been well mapped, candidate genes within the region can be examined for their possible involvement in the disease process. If the number of affected individuals is sufficient to allow us to narrow the candidate region to 1-2 cM, then physical mapping and cloning strategies will be used to isolate the defective gene.
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