Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria.
Homocystinuria is an autosomal recessive inborn error of metabolism that is most often caused by mutation in the cystathionine beta-synthase (CBS) gene. Patients may develop serious clinical manifestations such as lens dislocation, mental retardation, osteoporosis, and atherothrombotic vascular disease. Over 100 mutations have been reported, but so far, none have been reported in Korea. Mutation analysis of the CBS gene in six Korean patients with homocystinuria was performed by direct sequencing. Eight mutations were identified, including four known mutations (T257M, R336C, T353M, and G347S) and four novel mutations (L154Q, A155V, del234D, and A288T). All patients were compound heterozygotes. To characterize these mutations, normal or mutated forms of CBS were cloned into pcDNA3.1 expression vector followed by transfection into mammalian cells for transient expression. Whereas the expression levels of mutant proteins were comparable to that of normal control, enzyme activities of all the mutant forms were significantly decreased. In addition, a novel single nucleotide polymorphism, R18C, was identified, which showed one-third to two-thirds the enzyme activity of wild type and 1% of the allele frequency in normal control. The spectrum of mutations observed in Korean patients bears less resemblance to those observed in Western countries.
Lee
Sook-Jin
SJ
Division of Genetic Disease, Department of Biomedical Sciences, National Institute of Health, Seoul, South Korea.
Lee
Dong Hwan
DH
Yoo
Han-Wook
HW
Koo
Soo Kyung
SK
Park
Eun-Sook
ES
Park
Joo-Won
JW
Lim
Hun Gil
HG
Jung
Sung-Chul
SC
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005838:Genotype; D006712:Homocystinuria / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007723:Korea / Q000453:epidemiology; D051379:Mice; D041681:NIH 3T3 Cells; D010641:Phenotype
D003541:Cystathionine beta-Synthase