Homocystinuria
In a 20-year-old woman with pyridoxine-responsive homocystinuria (236200), Kluijtmans et al. (1996) identified a homozygous 1330G-A transition in the CBS gene, resulting in an asp444-to-asn (D444N) substitution in the regulatory domain of the protein. She was first admitted to the hospital at the age of 9 years because of psychomotor retardation, marfanoid features with excessive height, dolichostenomelia, arachnodactyly, and homocystinuria. She was treated with pyridoxine, folic acid, and betaine, with favorable results. Eleven years later she was in very good physical condition and her intellectual development had reached an average level. Ectopia lentis, osteoporosis, and vascular complications had not occurred. Both parents and an unaffected sister were heterozygous for the mutation. Despite the homozygous mutation, CBS activities in extracts of cultured fibroblasts of this patient were not in the homozygous but in the heterozygous range. In vitro functional expression studies showed no stimulation of CBS activity by S-adenosylmethionine, contrary to a 3-fold stimulation in control fibroblast extract. These data suggested that the D444N mutation interfered with S-adenosylmethionine regulation of CBS. Furthermore, it indicated the importance of S-adenosylmethionine regulation of the transsulfuration pathway in homocysteine homeostasis in humans.
CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Their functional importance is underlined by the finding that mutations in conserved residues within them cause a variety of human hereditary diseases, including homocystinuria. Scott et al. (2004) showed that tandem pairs of CBS domains from cystathionine beta-synthase, as well as the CBS domains from at least 3 other proteins that are the sites of mutations causing hereditary diseases, bind AMP, ATP, or S-adenosylmethionine, whereas mutations that cause hereditary diseases impair this binding. An interesting feature of the pathogenic mutations in CBS domains is that they tend to occur in equivalent positions. Thus, 3 mutations in the PRKAG2 gene that cause disease--R302Q (602743.0001), H383R, and R531G (602743.0006)--all align (plus or minus 1 residue) with the D444N mutation in the CBS gene.
Hyperhomocysteinemia, Thrombotic, CBS-related
In a patient with early-onset stroke and hyperhomocysteinemia without other manifestations of homocystinuria (see 236200), Kelly et al. (2003) identified a heterozygous D444N mutation. The patient was a 39-year-old Venezuelan man who had a retinal artery occlusion due to an arterial dissection. An unaffected sister was also heterozygous for the mutation. The presence of a second mutation could not be excluded.
