Impaired Heme Binding and Aggregation of Mutant Cystathionine β-Synthase Subunits in Homocystinuria

Jánošík, Miroslav; Oliveriusová, Jana; Janošı́ková, Bohumila; Sokolová, Jitka; Kraus, Eva; Kraus, Jan P.; Kožich, Viktor

doi:10.1086/320597

Cited by 77 publications

(102 citation statements)

References 21 publications

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“…1). In fact, these four mutations are particularly prevalent in certain populations Kluijtmans et al, 1999;Janosik et al, 2001; and this study]. G307S is prevalent in Ireland (71%), I278T in the Netherlands (55%), T191M in the Iberian Peninsula (50%), and IVS11-2A>C in Germany (20%) and in the former Czechoslovakia (19%).…”

Section: T191m Is a Prevalent Iberian Cbs Allelementioning

confidence: 57%

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

et al. 2003

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Homocystinuria due to cystathionine β-synthase (CBS) deficiency has been extensively studied, but to date, no spectrum of CBS mutations of Spanish homocystinuric patients has been reported. Here we present a mutation analysis of thirteen Spanish and three Portuguese unrelated homocystinuric patients. Ten mutations were found to account for the thirty-two mutant alleles and five of these (C275Y, L338P, S349N, R379Q, and L456P) are reported here for the first time. All five novel mutations were found to affect evolutionarily conserved residues suggesting that they may impair enzyme function. Interestingly, neither of the two common CBS mutations, I278T and G307S, was detected in this series, and no patient was found to respond to pyrodoxine. Enzyme activities in cultured fibroblasts from 10 of the patients were assayed, and they ranged from 0 to 13 % of controls analyzed in parallel. The T191M mutation (which has only ever been reported once before in a Spanish patient) accounted for 50% of the mutant alleles. Comparison of the clinical data of seven patients homozygous for T191M indicated that this genotype is a poor predictor of the phenotype. A common haplotype was identified in all the T191M chromosomes of Spanish origin, while a different one was present in the four T191M chromosomes from Portuguese patients.

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Section: T191m Is a Prevalent Iberian Cbs Allelementioning

confidence: 57%

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

et al. 2003

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“…The N-terminal domain binds the heme cofactor, which is axially coordinated by C52 and H65. The role of heme in CBS is not fully understood, and both structural and regulatory functions have been attributed to it (10)(11)(12)(13). However, CBS from lower eukaryotes, such as yeast, lacks heme entirely, thus clearly indicating that is not essential for catalytic activity (14,15).…”

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confidence: 99%

Structural basis of regulation and oligomerization of human cystathionine β-synthase, the central enzyme of transsulfuration

Ereño‐Orbea

Majtán

Oyenarte

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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163

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Cystathionine β-synthase (CBS) controls the flux of sulfur from methionine to cysteine, a precursor of glutathione, taurine, and H 2 S. CBS condenses serine and homocysteine to cystathionine with the help of three cofactors, heme, pyridoxal-5′-phosphate, and S-adenosyl-L-methionine. Inherited deficiency of CBS activity causes homocystinuria, the most frequent disorder of sulfur metabolism. We present the structure of the human enzyme, discuss the unique arrangement of the CBS domains in the C-terminal region, and propose how they interact with the catalytic core of the complementary subunit to regulate access to the catalytic site. This arrangement clearly contrasts with other proteins containing the CBS domain including the recent Drosophila melanogaster CBS structure. The absence of large conformational changes and the crystal structure of the partially activated pathogenic D444N mutant suggest that the rotation of CBS motifs and relaxation of loops delineating the entrance to the catalytic site represent the most likely molecular mechanism of CBS activation by S-adenosyl-L-methionine. Moreover, our data suggest how tetramers, the native quaternary structure of the mammalian CBS enzymes, are formed. Because of its central role in transsulfuration, redox status, and H 2 S biogenesis, CBS represents a very attractive therapeutic target. The availability of the structure will help us understand the pathogenicity of the numerous missense mutations causing inherited homocystinuria and will allow the rational design of compounds modulating CBS activity.

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“…The milder phenotype and late age of diagnosis in patients carrying the c.833T>C allele was apparent also in our study; of the three patients who fell outside the birth cohort used for incidence calculations, two were diagnosed in adulthood and both were homozygous for the c.833T>C allele. Of interest, there is a gradient in severity throughout the patient population, there are more severely affected patients in Slovakia, and more patients with a milder phenotype in the Czech Republic (Janošík et al, 2001). This difference may have resulted from varying diagnostic criteria in the two countries or it might have represented a gradient in allele frequency around the region.…”

Section: Discussionmentioning

confidence: 99%

“…In these patients, the pathogenic sequence variants were determined by DNA sequencing as described elsewhere (Janošík et al, 2001).…”

Section: Samples and Dna Isolationmentioning

confidence: 99%

Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

Sokolová¹,

Janošı́ková²,

Terwilliger³

et al. 2001

Hum. Mutat.

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Recent reports suggested that homocystinuria due to cystathionine beta-synthase (CBS) deficiency is a more common inborn error of metabolism than originally thought. In this study we compared the prevalence of homocystinuric alleles ascertained by two different approaches. First, the incidence of homocystinuria estimated by selective biochemical screening in the Czech and Slovak Republics was 1:349,000 (95% CI 1:208,000-1:641,000). The two most common pathogenic mutant alleles found subsequently in these patients, IVS11-2A>C and c.833T>C, had a calculated population prevalence of 0.00042 (95% CI 0.00031-0.00055) and 0.00018 (95% CI 0.00013-0.00023), respectively. Second, to examine the possible negative detection bias of mildly affected patients we determined the prevalence of these two pathogenic mutations in a sample of 1284 unselected newborns. Indeed, the observed prevalence of the c.833T>C allele (0.00195, 95% CI 0.00063-0.00454) was 11x higher than in the previous group suggesting that many homozygotes for the c.833T>C had not been diagnosed by selective biochemical screening. The IVS11-2A>C allele was not detected among 2,568 newborn CBS alleles. The estimated incidence of homocystinuria of 1:83,000, calculated in a combined model, suggests that selective biochemical screening may ascertain only ~25% of all homocystinuric patients. In conclusion, homocystinuria in Central Europe may be sufficiently common to consider sensitive newborn screening programs for this disease.

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Impaired Heme Binding and Aggregation of Mutant Cystathionine β-Synthase Subunits in Homocystinuria

Cited by 77 publications

References 21 publications

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

Structural basis of regulation and oligomerization of human cystathionine β-synthase, the central enzyme of transsulfuration

Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

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