The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.
Cystathionine beta-synthase (CBS) deficiency is the most common cause of homocystinuria. It is inherited as an autosomal recessive trait and common clinical features are: dislocation of the optic lens, osteoporosis, mental retardation, and thromboembolism. We determined the molecular basis of CBS deficiency in 36 Australian patients from 28 unrelated families, using direct sequencing of the entire coding region of the CBS gene. The G307S and I278T mutations were the most common mutations. They were present in 19% and 18% of independent alleles, respectively. In total, seven novel and 20 known mutations were detected. Of those, the two novel missense mutations (C109R and G347S), as well as two known missense mutations (L101P and N228K), were expressed in E. Coli. All mutant proteins completely lacked catalytic activity. Furthermore, we studied the correlation between genotype and the biochemical response to pyridoxine treatment in the patients of whom 13 were pyridoxine responsive, 21 were non-responsive, and two were partially responsive. The G307S mutation always resulted in a severe non-responsive phenotype, whereas I278T resulted in a milder B6 responsive phenotype. From our results, we were also able to establish three other mild mutations: P49L, R369C, and V371M.
Cardiovascular Genetics Laboratory, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Mette
M
Gaustadnes
Bridget
B
Wilcken
Jana
J
Oliveriusova
Jim
J
McGill
Janice
J
Fletcher
Jan P
JP
Kraus
David E
DE
Wilcken
D000293:Adolescent; D000328:Adult; D001315:Australia / Q000453:epidemiology; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003541:Cystathionine beta-Synthase / Q000032:analysis / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004334:Drug Administration Schedule; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D006580:Genetic Carrier Screening; D005838:Genotype; D006712:Homocystinuria / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011736:Pyridoxine / Q000008:administration & dosage / Q000627:therapeutic use
D005492:Folic Acid; D003541:Cystathionine beta-Synthase; D011736:Pyridoxine