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© 1994 Oxford University Press

OTHER

Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine ß-synthase using an improved bacterial expression system

Raffaella de Franchis, Viktor Kozich, Roderick R. Mcinnes1 and Jan P. Kraus*

Department of Pediatrics, University of Colorado School of Medicine Denver, CO 80262, USA 1Departments of Pediatrics and Genetics, The Hospital for Sick Children Toronto, Ontario M5G 1X8, Canada

*To whom correspondence should be addressed

Received March 7, 1994; Revised May 16, 1994; Accepted May 16, 1994

We determined the molecular basis of cystathionine ß-synthase (CBS) deficiency in three siblings with pyridoxine responsive homocystinuria using a significantly improved mutation screening method in bacteria. The phenotypic expression of the siblings differed even though their CBS genotypes were identical. The paternal allele contained a linked pair of mutations, C233G and G306C, corresponding to P78R and K102N in the polypeptide chain. Together, these inactivated the enzyme; however, expressed separately, they reduced activity by about one half. The single maternal mutation G715A (E239K) effectively abolished CBS activity. Subunits of CBS were absent from patient fibroblast extracts; however, E.coll, transformed with plasmids containing patient CBS cDNA, expressed the subunits, although in reduced amounts. The mother, an obligate heterozygote, was free from all signs of homocystinuria; nonetheless, extracts of her fibroblasts were devoid of CBS protein and activity. We conclude that fibroblast levels of CBS are only partially effective as prognosticators of disease severity and that it is important to test the in vivo response to vitamin B6 in all cases of homocystinuria, including those in which the mutations lead to the absence of the enzyme in cultured fibroblasts.


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