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Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected].

ABSTRACT: β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.

SUBMITTER: Nakajima Y

PROVIDER: S-EPMC4158181 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Protein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown. METHODS: Thirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis. RESULTS: A total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C>T (rs146922325:C>T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI?=?1.1-71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88% patients and in 0.87% controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR?=?7.34, 95%CI?=?3.61-14.94). The plasma PC activity and antigen levels in heterozygotes were 51.73±6.92 U/dl and 75.17±4.84 U/dl, respectively. CONCLUSIONS: This is the first study on the genetic background of PC deficiency in the Chinese population. The PROC c.565C>T mutation is the most frequent cause of PC deficiency as well as a prevalent risk factor for VT in Chinese individuals. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis.

Dataset Information

Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation [corrected].

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