Spinal Muscular Atrophy (SMA) is an inherited neuromuscular disorder of the alpha motoneuron. The early onset forms are clearly inherited in an autosomal recessive pattern which are second in frequency to cystic fibrosis among heritable disorders affecting children. Later onset forms are more likely to follow an autosomal dominant pattern of inheritance. All SMA cases are characterized by symmetrical limb muscle weakness/atrophy, evidence of denervation, and anterior horn cell degeneration. The most severe form of SMA, Werdnig-Hoffmann disease (Acute SMA, or SMA type I), presents in the first months of life and is fatal by four years, if not earlier. Later onset cases generally have more benign phenotypes. For decades clinicians have debated over diagnostic criteria for the various forms of SMA, and whether they are the result of non-allelic mutations producing a common phenotype, or whether the SMAs are a monogenic disorder with variable phenotypic expression. In the past three years we have collected and """"""""banked"""""""" over 500 transformed lymphocyte cell lines from SMA families. The SMA cell bank includes 4 multiple affected, 9 three affected, and 30 two affected chronic SMA families along with 8 consanguineous marriage Werdnig-Hoffmann families and several families with dominantly inherited late onset SMA. We have typed the most informative families with about 100 DNA markers and karyotyped chromosomes of 50 SMA patients as part of a gene mapping effort to locate the disease locus or loci which causes SMA. In this proposal we outline a strategy to genetically map the locus (loci) for all types of SMA including the genetically unavailing acute form(s), as well as a plan to evaluate genetic heterogeneity among SMA families. Molecular and genetic strategies are presented to focus and characterize the disease locus (loci) with the ultimate goal of identifying the abnormal gene product(s) responsible for Spinal Muscular Atrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028877-03
Application #
3415570
Study Section
Neurology C Study Section (NEUC)
Project Start
1990-09-10
Project End
1995-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Carter, T A; Bonnemann, C G; Wang, C H et al. (1997) A multicopy transcription-repair gene, BTF2p44, maps to the SMA region and demonstrates SMA associated deletions. Hum Mol Genet 6:229-36
Wang, C H; Carter, T A; Das, K et al. (1997) Extensive DNA deletion associated with severe disease alleles on spinal muscular atrophy homologues. Ann Neurol 42:41-9
Wang, C H; Xu, J; Carter, T A et al. (1996) Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy. Hum Mol Genet 5:359-65
Wang, C H; Kleyn, P W; Vitale, E et al. (1995) Refinement of the spinal muscular atrophy locus by genetic and physical mapping. Am J Hum Genet 56:202-9
Selig, S; Bruno, S; Scharf, J M et al. (1995) Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene. Proc Natl Acad Sci U S A 92:3702-6
Tanzi, R E; Petrukhin, K; Chernov, I et al. (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344-50
Petrukhin, K; Fischer, S G; Pirastu, M et al. (1993) Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet 5:338-43
Rojas, K; Straub, R E; Kurtz, A et al. (1992) Identification and localization of microsatellite markers covering human chromosome 18. Genomics 14:1095-7
Kleyn, P W; Brzustowicz, L M; Wilhelmsen, K C et al. (1991) Spinal muscular atrophy is not the result of mutations at the beta-hexosaminidase or GM2-activator locus. Neurology 41:1418-22