© 1993 Oxford University Press
RESEARCH-ARTICLE |
Molecular basis of cystathionine ß-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria
ich21Neurology Service, Massachusetts General Hospital Boston, MA 02129 2Pediatrics and Cellular/Structural Biology, University of Colorado School of Medicine Denver, CO 80262 3Molecular Neurogenetics Unit, Massachusetts General Hospital Boston, MA 02129 4Department of Neurology, Harvard Medical School Boston, MA 02114, USA
*To whom correspondence should be addressed at: Amino Acid Disorder Laboratory, Massachusetts General Hospital, Building 149, 13th Street, Boston, MA 02129, USA
Received July 12, 1993; Revised September 17, 1993; Accepted September 17, 1993
Cystathionine ß-synthase (CBS) deficiency is an autosomal recessive disorder associated with multisystem clinical disease. We analyzed PCR amplified products from patients' RNA and genomic DNA. Direct sequencing of the entire coding region of the CBS gene revealed a G-919 to A transition in exon 8, resulting in replacement of Gly 307 by Ser (G307S) in the protein. The mutation was detected in one allele of patient L171 of French/Scottish ancestry and in both alleles of patient L198 of irish ancestry. Amplifying and sequencing exon 8 from the genomic DNA showed that both parents of L198 were heterozygotes for G307S. The pathogenicity of the mutation was demonstrated in an expression experiment. The mutant protein was apparently stable in E.coll extracts and lacked catalytic activity. Sequencing of exon 8 revealed the G307S mutation in five additional families. All patients have pyridoxine nonresponsive homocystinuria. We have now observed this mutation in 9 of 52 apparently unrelated alleles of varied ethnic backgrounds. All 9 are from patients with Celtic (Irlsh/English/Scottish/French) ancestry in either one or both parents. The G307S mutation was detected in 50% (9 of 18) of the Celtic alleles in our series. The second mutation found in exon 8 is the 1278T mutation, which was described previously in one allele of a pyridoxine responsive patient. This missense mutation was detected in one allele of a pyridoxine nonresponsive patient and in both alleles of a pyridoxine responsive patient. The latter suggests that 1278T is probably associated with pyridoxine responsiveness.
+Present address: Howard Hughes Medical Institite, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA
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