Journal Article

Variation in the Biochemical/Biophysical Properties of Mutant Superoxide Dismutase 1 Enzymes and the Rate of Disease Progression in Familial Amyotrophic Lateral Sclerosis Kindreds

Tamara Ratovitski, Laura B. Corson, Jeffrey Strain, Philip Wong, Don W. Cleveland, Valeria C. Culotta and David R. Borchelt

in Human Molecular Genetics

Volume 8, issue 8, pages 1451-1460
Published in print August 1999 | ISSN: 0964-6906
Published online August 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.8.1451
Variation in the Biochemical/Biophysical Properties of Mutant Superoxide Dismutase 1 Enzymes and the Rate of Disease Progression in Familial Amyotrophic Lateral Sclerosis Kindreds

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Mutations in superoxide dismutase 1 (SOD1) polypeptides cause a form of familial amyotrophic lateral sclerosis (FALS). In different kindreds, harboring different mutations, the duration of illness tends to be similar for a given mutation. For example, patients inheriting a substitution of valine for alanine at position four (A4V) average a 1.5 year life expectancy after the onset of symptoms, whereas patients harboring a substitution of arginine for histidine at position 46 (H46R) average an 18 year life expectancy after disease onset. Here, we examine a number of biochemical and biophysical properties of nine different FALS variants of SOD1 polypeptides, including enzymatic activity (which relates indirectly to the affinity of the enzyme for copper), polypeptide half-life, resistance to proteolytic degradation and solubility, in an effort to determine whether a specific property of these enzymes correlates with clinical progression. We find that although all the mutants tested appear to be soluble, the different mutants show a remarkable degree of variation with respect to activity, polypeptide half-life and resistance to proteolysis. However, these variables do not stratify in a manner that correlates with clinical progression. We conclude that the basis for the different life expectancies of patients in different kindreds of sod1-linked FALS may result from an as yet unidentified property of these mutant enzymes.

Journal Article.  7814 words.  Illustrated.

Subjects: Genetics and Genomics

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