Hexosaminidase (HEX) deficiency causes several neurological disease phenotypes including spinal muscular atrophy and an ALS- like disorder in adults, cerebellar ataxia in children, and in infants dementia, seizures, and retinopathy. At least three gene loci are required for full HEX activity and defects at each can cause disease. This project is focused on defining the specific gene defects and peptide defects in our large group of patients with HEX deficiency disease. For the most part we will study patients' fibroblasts in culture. We have transformed with SV-40 a large group of HEX deficient patients' fibroblasts cultured from skin. Defects of regulatory genes cannot be easily studied in humans at present. Therefore, we have turned to the best available mammalian system, inbred mice, to study HEX regulation, especially temporal regulation, which may be important for some of our late-onset HEX deficient patients. We plan to compare HEX cDNA sequences and later genomic sequences from two inbred mouse strains which show genetically determined differences in HEX expression. We are taking advantage of four new tools which we have developed: 1. A new system for study HEX regulation, 2. A new method of peptide mapping using in situ CNBr cleavage, 3. Anti-HEX beta subunit monoclonal antibodies we recently raised, so far as we know the first anti-HEX monoclonals made, 4. A unique HEX beta-gene sequence which we recently cloned and have characterized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS015281-09A1
Application #
3396080
Study Section
Neurology C Study Section (NEUC)
Project Start
1979-03-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
9
Fiscal Year
1987
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
Johnson, W G (1991) Genetic susceptibility to Parkinson's disease. Geriatrics 46 Suppl 1:52-9
Johnson, W G; Yoshidome, H; Stenroos, E S et al. (1991) Origin of the neuron-like cells in tuberous sclerosis tissues. Ann N Y Acad Sci 615:211-9
Johnson, W G (1991) Genetic susceptibility to Parkinson's disease. Neurology 41:82-7;discussion 88
Johnson, W G; Hodge, S E; Duvoisin, R (1990) Twin studies and the genetics of Parkinson's disease--a reappraisal. Mov Disord 5:187-94
Johnson, W G; Hong, J L (1986) Variation in alpha-L-fucosidase properties among 28 inbred mouse strains: six strains have high enzyme activity and heat-stabile enzyme with a variant pH-activity curve;twenty-two strains have low activity and heat-labile enzyme. Biochem Genet 24:469-83
Johnson, W G; Hong, J L; Knights, S M (1986) Variation in ten lysosomal hydrolase enzyme activities in inbred mouse strains. Biochem Genet 24:891-909
Neuwelt, E A; Johnson, W G; Blank, N K et al. (1985) Characterization of a new model of GM2-gangliosidosis (Sandhoff's disease) in Korat cats. J Clin Invest 76:482-90