Molecular basis of phenotype expression in homocystinuria

@article{Kraus2004MolecularBO,
  title={Molecular basis of phenotype expression in homocystinuria},
  author={Jan P Kraus},
  journal={Journal of Inherited Metabolic Disease},
  year={2004},
  volume={17},
  pages={383-390}
}
  • J. Kraus
  • Published 1 July 1994
  • Biology
  • Journal of Inherited Metabolic Disease
SummaryCystathionine β-synthase (CBS) deficiency is the most common cause of homocystinuria in humans. The human gene maps to chromosome 21q22.3 and encodes the CBS subunit of 551 amino acid residues (63 kDa). CBS, a tetramer of these subunits, binds its two substrates, homocysteine and serine, and three additional ligands: pyridoxal 5′-phosphate,S-adenosylmethionine, and haem. Screening for mutations by expressing patient cDNA segments inE. coli permitted us to separate the parental CBS… Expand
Two novel missense mutations in the cystathionine β-synthase gene in homocystinuric patients
TLDR
Direct sequencing of the coding region of the cystathionine β-synthase (CBS) gene in two homocystinuric patients revealed the presence of two novel missense mutations, found in a compound heterozygous state with the previously described 833T → C transition. Expand
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We describe four new mutations in the cystathionine β-synthase gene: three point mutations localized in exons 3, 9 and 10 and one mutation in exon 12 which results in stop codon. Homocystinuria dueExpand
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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Cystathionine β-synthase (CBS), the pivotal enzyme of the reverse transsulfuration pathway, catalyzes the pyridoxal-5’-phosphate-dependent condensation of serine with homocysteine to formExpand
Hyperhomocysteinemia and dyslipidemia in point mutation G307S of cystathionine β-synthase-deficient rabbit generated using CRISPR/Cas9
TLDR
A CBS G307S rabbit model was generated that exhibited severe dyslipidemia when fed on a normal diet, indicating that G 307S mutation in the CBS gene is a causative factor for dyslipids. Expand
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References

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Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells.
TLDR
The human CBS cDNA sequence of 2,554 nucleotides encoding the CBS subunit of 551 amino acids is reported and it is demonstrated that expression of the human enzyme in CHO cells yields enzymatically active protein of the expected size with a half-life of approximately 14 hrs. Expand
Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria.
TLDR
The G307S mutation was detected in 50% (9 of 18) of the Celtic alleles in the authors' series, which suggests that Celtic (Irish/English/Scottish/French) ancestry in either one or both parents is probably associated with pyridoxine responsiveness. Expand
Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B6 nonresponsive homocystinuria.
TLDR
Using SSCP to survey reverse transcribed-PCR amplified cystathionine synthase cDNAs from patients with homocystinuria, one synonymous and two missense mutations in a portion of the cDNA encoded by a single 135 bp exon suggest they may have arisen by a gene conversion event or by nonhomologous recombination. Expand
Screening for mutations by expressing patient cDNA segments in E. coli: Homocystinuria due to cystathionine β‐synthase deficiency
TLDR
This bacterial expression system proved to be a rapid screening method for localizing pathogenic mutations in CBS, allowing us to sequence the affected portions of mutant cDNA within 7–10 days of harvesting cultured fibroblasts. Expand
Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system.
TLDR
It is concluded that fibroblast levels of CBS are only partially effective as prognosticators of disease severity and that it is important to test the in vivo response to vitamin B6 in all cases of homocystinuria, including those in which the mutations lead to the absence of the enzyme in cultured fibroblasts. Expand
Assignment of the gene for cystathionine β-synthase to human chromosome 21 in somatic cell hybrids
TLDR
The results suggest that the human gene for CBS, called CBS, and thus for the most common form of homocystinuria, is located on chromosome 21. Expand
The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17.
TLDR
The human gene for cystathionine beta-synthase (CBS) and the gene for alpha A-crystalline (CRYA1/Crya-1 or Acry-1) form a conserved linkage group on human (HSA) chromosome region 21q22.3 and mouse (MMU) chromosome 17 region A-C. Expand
Rat cystathionine beta-synthase: expression of four alternatively spliced isoforms in transfected cultured cells.
TLDR
The gene for rat cystathionine beta-synthase consists of 17 exons and its transcripts are alternatively spliced, forming four distinct mRNA species, which elucidates the mechanism by which AdoMet regulates synthase activity. Expand
Rat cystathionine beta-synthase. Gene organization and alternative splicing.
TLDR
The structure and alternative splicing patterns of the rat cystathionine beta-synthase gene are elucidated, and synthase shows substantial sequence similarity with pyridoxal 5'-phosphate dependent enzymes from lower organisms. Expand
Expression of human cystathionine beta-synthase in Escherichia coli: purification and characterization.
TLDR
Human CBS cDNA is cloned in tandem with the beta-galactosidase sequence of the fusion vector, pAX5-, then the fusion protein is expressed in transformed Escherichia coli cells, marking the first time this enzyme has been isolated in sufficient quantities for biophysical and biochemical investigation. Expand
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