title: Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH).
abstract: Hereditary cystathioninuria (MIM 219500) is presumed to be caused by deficiency of the activity of cystathionine gamma-lyase (cystathionase; CTH EC 4.4.1.1), which is normally required for the conversion of methionine into cysteine. To date, no mutations have been described among patients with cystathioninuria. From genomic DNA, we sequenced CTH in four unrelated probands with cystathioninuria. We found two nonsense mutations, namely exon 8 c.940-941delCT and exon 11 c.1220delC, and two missense mutations, namely exon 2 c.356C>T (T67I) and exon 7 c.874C>G (Q240E). All affected subjects were either simple homozygotes or compound heterozygotes. A common non-synonymous single nucleotide polymorphism in exon 12, namely c.1364G>T (S403I), was also identified and characterized in four ethnic groups. The reagents described in this report make the molecular diagnosis of cystathioninuria possible, allowing for studies of phenotype-genotype correlation. Also, the availability of a common non-synonymous SNP can allow for testing of association of the CTH gene with biochemical traits affected by trans-sulfuration, such as plasma concentrations of homocysteine or even cystathionine itself, in addition to more downstream clinical phenotypes, such as vascular disease.
authors.affiliation: Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, N6A 5K8, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D018389:Codon, Nonsense; D003540:Cystathionine / Q000235:genetics* / Q000652:urine*; D003542:Cystathionine gamma-Lyase / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008214:Lymphocytes; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D003540:Cystathionine; D003542:Cystathionine gamma-Lyase