Myotonic muscular dystrophy (MyD) is the most prevalent human muscular dystrophy affecting several hundred thousand individuals in the United States. It is inherited as an autosomal dominant trait and is characterized by variable expressivity and late age-of-onset (birth to 70 years). The delineation of a restriction fragment length polymorphism (RFLP) that is closely linked (0 less than or equal to 0.01) to the locus for MyD would have immediate medical application for heterozygote diagnosis before the age of onset of symptoms and signs, as well as family planning and prenatal diagnosis. We propose to screen a chromosome 19 library using two experimental strategies: random screening and chromosome walking from a known linked polymorphism. We will use the linkage data available from several polymorphisms (Complement component 3, ABH secretor, Lewis, Lutheran, proline dipeptidase) in large multigenerational, tested MyD families to test the linkage of RFLPs as well as to determine the direction of chromosome walk. The walk has been initiated from a 1.4 kb unique sequence of complement component 3, which is linked to MyD, and a haplotype or """"""""HLA-like"""""""" set of polymorphisms will be delineated as the reiterated walking procedure is continued. When a closely linked RFLP is determined (either from walking or by random screening of the chromosome 19 library), a useful probe for heterozygote diagnosis will be then available for clinical application and testing in a large population of MyD families. Methods of RNA selection and gene product analysis can then be instituted to examine the closely linked area of the chromosome to identify the mutation(s) responsible for MyD and to develop rational therapy. These experiments will also be useful in contributing linkage map information about chromosome 19, a relatively unstudied part of the human genome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019999-03
Application #
3400153
Study Section
Molecular Biology Study Section (MBY)
Project Start
1983-07-01
Project End
1986-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Samson, F; Mesnard, L; Mihovilovic, M et al. (1994) A new human slow skeletal troponin T (TnTs) mRNA isoform derived from alternative splicing of a single gene. Biochem Biophys Res Commun 199:841-7
Roses, A D (1993) Molecular genetics of neurodegenerative diseases. Curr Opin Neurol Neurosurg 6:34-9
Kazantsev, A; Yamaoka, L H; Roses, A D (1992) A dinucleotide repeat polymorphism in the human Na+,K+ ATPase, alpha subunit (ATP1A3) gene. Nucleic Acids Res 20:1164
Samson, F; de Jong, P J; Trask, B J et al. (1992) Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis. Genomics 13:1374-5
Gilbert, J R; Stajich, J M; Speer, M C et al. (1992) Linkage studies in facioscapulohumeral muscular dystrophy (FSHD). Am J Hum Genet 51:424-7
Speer, M C; Yamaoka, L H; Gilchrist, J H et al. (1992) Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: linkage of an autosomal dominant form to chromosome 5q. Am J Hum Genet 50:1211-7
Secore, S L; Walker, A P; Herbstreith, M H et al. (1991) A StuI polymorphism on chromosome 3p14.1-14.2 (D3S622) defined by two polymorphic StuI sites 2.4 kb apart. Nucleic Acids Res 19:6349
Samson, F; Gilbert, J R; Koza-Taylor, P et al. (1991) A PstI polymorphism detected by a genomic clone at the human slow troponin T (TNNT1) gene locus. Nucleic Acids Res 19:6058
Speer, M C; Pericak-Vance, M A; Yamaoka, L et al. (1990) Presymptomatic and prenatal diagnosis in myotonic dystrophy by genetic linkage studies. Neurology 40:671-6
Roses, A D; Pericak-Vance, M A; Clark, C M et al. (1990) Linkage studies of late-onset familial Alzheimer's disease. Adv Neurol 51:185-96

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