Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan

Kira, Ryutaro; Ihara, Kenji; Watanabe, Kyoko; Kanemitsu, Shigeru; Ahmed, Sharmeen; Gondo, Kenjiro; Takeshita, Kenzo; Hara, Toshiro

doi:10.1007/s100380050119

Cited by 20 publications

(11 citation statements)

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“…Thus, the frequency of the 446GϾT (Trp149Stop) polymorphism of the ARLTS1, a member of the ADP ribosylation family, was similar in controls and patients with sporadic tumors but was significantly more common among patients with familial cancer. 26 Finally, the common nonsense polymorphism affecting the complement C9 gene (Arg95Stop), which is present in 6.7% of the Japanese population, 27 causes complement deficiency when present in homozygous state. Other polymorphisms affecting serpin-encoding genes might cause deficiency of the affected protein.…”

Section: Zpi R67x Polymorphism Increases Dvt Riskmentioning

confidence: 99%

A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

Corral

Gónzález-Conejero

Soria

et al. 2006

Blood

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The protein Z-dependent protease inhibitor (ZPI) is a hemostatic serpin with anticoagulant activity. As for antithrombin, deficiency of ZPI could have relevant thrombotic consequences. We have studied 6 genetic modifications affecting the ZPI gene, identifying 5 haplotypes. Haplotype H5 is featured by a stop codon at position 67. The relevance of these genetic modifications and haplotypes in venous thrombosis was evaluated in a case-control study including 1018 patients and 1018 age-and sex-matched controls. Surprisingly, the H5 haplotype was found in 0.9% of controls, supporting that the Arg67Stop change is a low frequency nonsense polymorphism. The prevalence of this haplotype increased significantly in patients (3.0%), one of whom was in a homozygous state. Multivariate analysis confirms that carriers have a 3.3-fold risk of developing venous thrombosis (P ‫؍‬ .002; 95% CI: 1.5-7.1). Moreover, we observed a significant association of this polymorphism with familial history of thrombosis (P < .001). Our study supports that the ZPI Arg67Stop nonsense polymorphism might be an independent genetic risk factor for venous thrombosis. This polymorphism has slightly lower prevalence but similar thrombotic risk than the FV Leiden or prothrombin 20210A. Although further studies are required, all available data support that the ZPI is a candidate to play a significant role in thrombosis and should be evaluated in thrombophilic studies. (Blood. 2006;108:177-183)

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Section: Zpi R67x Polymorphism Increases Dvt Riskmentioning

confidence: 99%

A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

Corral

Gónzález-Conejero

Soria

et al. 2006

Blood

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“…[73][74][75][76] Similarly, their sera possess some bactericidal activity, although the rate of killing is significantly reduced. Whether activated by the classical or alternative pathways, C3 is cleaved into two fragments of unequal sizes.…”

Section: C3 Deficiencymentioning

confidence: 99%

“…74,77 A nonsense mutation in exon 4 has a gene frequency of 1 : 1,000 in Japanese populations. 74,77 A nonsense mutation in exon 4 has a gene frequency of 1 : 1,000 in Japanese populations.…”

Section: C3 Deficiencymentioning

confidence: 99%

Complement Deficiencies

Sullivan¹

2016

Pediatric Allergy: Principles and Practice

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“…The Japanese genomic DNA samples were from 100 normal children, 18 heterozygotes for the R95X mutation and five C9D patients (homozygotes), whose genotypes were determined in our previous studies (Kira et al 1998(Kira et al , 1999. The Japanese genomic DNA samples were from 100 normal children, 18 heterozygotes for the R95X mutation and five C9D patients (homozygotes), whose genotypes were determined in our previous studies (Kira et al 1998(Kira et al , 1999.…”

Section: Study Subjectsmentioning

confidence: 99%

Founder effect of the C9 R95X mutation in Orientals

et al. 2003

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A nonsense mutation at codon 95 (R95X) in the C9 gene is responsible for most Japanese C9 deficiency (C9D) cases, with a carrier frequency of 6.7%. Upon analysis of microsatellite markers and newly identified dinucleotide repeat number polymorphisms in the 3′ flanking region of the C9 gene, a founder effect was demonstrated for the R95X mutation of the C9 gene in Japanese. Screening for the R95X mutation in Korean and Chinese individuals showed that the R95X carrier frequencies in Koreans and Chinese were 2.0% and 1.0%, respectively. Although homozygotes for the R95X mutation were not found in Korea or China, the shared haplotype of the dinucleotide repeat number polymorphisms appeared to be associated with the R95X mutation in the heterozygotes in Korea and China. The founder effect found in East Asians (Japanese, Koreans and Chinese) but not in Caucasians, as well as the haplotype sharing in only a small chromosomal interval, suggested that the R95X mutation of C9 gene was ancient and had occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan. Since the mortality of meningococcal infections in complement-deficient patients is lower than that in normal individuals, a founder effect and a selective advantage in isolation might be the main reasons for the high frequency of the R95X mutation in Japan.

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Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan

Cited by 20 publications

References 5 publications

A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

Complement Deficiencies

Founder effect of the C9 R95X mutation in Orientals

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