𝔖 Bobbio Scriptorium
✦   LIBER   ✦

Four novel mutations in the cystathionine β-synthase gene: Effect of a second linked mutation on the severity of the homocystinuric phenotype

✍ Scribed by Raffaella de Franchis; Eva Kraus; Viktor Kozich; Gianfranco Sebastio; Jan P. Kraus

Publisher
John Wiley and Sons
Year
1999
Tongue
English
Weight
231 KB
Volume
13
Category
Article
ISSN
1059-7794

No coin nor oath required. For personal study only.

✦ Synopsis

Homocystinuria due to cystathionine b-synthase (CBS) deficiency is frequently caused by missense mutations. In this article, we report four novel missense mutations in the CBS gene: 172C®T (R58W) linked in cis with A114V; 376A®G (M126V); 904G®A (E302K); and 1006C®T (R336C). The CBS activity of the corresponding mutant enzymes expressed in Escherichia coli was greatly diminished, confirming the pathogenicity of these mutations. Western analysis showed that the R58W+A114V and M126V mutant enzymes were unstable in E. coli, while the E302K subunits were partially degraded to shorter products. Using site-directed mutagenesis we found that CBS containing either the R58W or A114V as the only mutations demonstrated 18% and 46% of normal activity, respectively. Both mutant forms of CBS were stable in E. coli. When these two mutations were expressed in cis, the resultant mutant protein exhibited activity 1.3% that of a control. All these in vitro results were in good agreement with the clinical manifestation in these patients. The Italian patient 2241, an A114V+R58W/M126V compound heterozygote, exhibited severe pyridoxine nonresponsive homocystinuria, while another Italian patient 2242, with an A114V/E302K genotype, responded to pyridoxine treatment and had a much milder phenotype. The third patient 3064, an English compound heterozygote for two severe mutations R336C and G307S, was B6 nonresponsive. This report of a ninth homocystinuric allele carrying two mutations in cis raises the possibility that double mutant alleles may be underestimated in homocystinuric patients. In this context, a search for additional mutations in cis may sometimes be necessary to establish a good genotype-phenotype relationship. Hum Mutat 13:453-457, 1999.

📜 SIMILAR VOLUMES

Mutational analysis of the cystathionine
Mutational analysis of the cystathionine β-synthase gene: A splicing mutation, two missense mutations and an insertion in patients with homocystinuria
✍ Ross B. Gordon; Anthony J. Cox; Paul A. Dawson; Bryan T. Emmerson; Jan P. Kraus; 📂 Article 📅 1998 🏛 John Wiley and Sons 🌐 English ⚖ 132 KB 👁 1 views

RT-PCR and direct sequence analyses were used to define mutations in the cystathionine b -synthase (CBS) gene in two unrelated male patients with vitamin B6 nonresponsive homocystinuria. Both patients were compound heterozygotes for CBS alleles containing point mutations. One patient had a maternall

Identification of novel missense mutatio
Identification of novel missense mutations in the Norrie disease gene associated with one X-linked and four sporadic cases of Familial Exudative Vitreoretinopathy
✍ Barkur S. Shastry; James F. Hejtmancik; Michael T. Trese 📂 Article 📅 1997 🏛 John Wiley and Sons 🌐 English ⚖ 173 KB 👁 2 views

X-linked Familial Exudative Vitreoretinopathy (XLFEVR) is a hereditary eye disorder that affects both the retina and the vitreous body. It is characterized by an abnormal vascularization of the peripheral retina. It has been previously shown by linkage and candidate gene analysis that XLFEVR and Nor

Haplotyping of wild type and I278T allel
Haplotyping of wild type and I278T alleles of the human cystathionine β-synthase gene based on a cluster of novel SNPs in IVS12
✍ Michael Linnebank; Anja Homberger; Jan Peter Kraus; Erik Harms; Viktor Kozich; H 📂 Article 📅 2001 🏛 John Wiley and Sons 🌐 English ⚖ 22 KB

Homocystinuria is most frequently due to deficiency of cystathionine β β -synthase (CBS). We identified IVS12 as a polymorphism hot spot of the human CBS gene and report five novel single nucleotide polymorphisms (SNPs): g.13514G>A, g.13617A>G, g.13715C>T, g.13800G>A, and g.13904C>T. Analyzing 50 co

X-linked Charcot–Marie–Tooth disease: Ph
X-linked Charcot–Marie–Tooth disease: Phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene
✍ Petr Vondracek; Pavel Seeman; Marketa Hermanova; Lenka Fajkusova 📂 Article 📅 2005 🏛 John Wiley and Sons 🌐 English ⚖ 74 KB

## Abstract We report a family with X‐linked dominant Charcot–Marie–Tooth disease (CMTX1). Three affected family members are described, who underwent detailed clinical, electrophysiological, molecular genetic, and histopathological studies. A novel isoleucine at position 127 with serine (Ile127Ser)

The spectrum of mutations, including fou
The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families
✍ Tal Raz; Valentina Labay; Dana Baron; Raymonde Szargel; Yefim Anbinder; Tim Barr 📂 Article 📅 2000 🏛 John Wiley and Sons 🌐 English ⚖ 244 KB 👁 3 views

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder with a triad of symptoms: megaloblastic anemia, deafness, and non-type 1 diabetes mellitus. Occasionally, cardiac abnormalities and abnormalities of the optic nerve and retina occur as well. Patients with TRMA often r