Two Distinct Novel Splice Site Mutations in a Compound Heterozygous Patient with Protein S Deficiency

Tomio Yamazaki; Akira Katsumi; Yoshihiro Okamoto; Toshio Takafuta; Shinobu Tsuzuki; Kazuo Kagami; Isamu Sugiura; Tetsuhito Kojima; Kingo Fujimura; Hidehiko Saito

doi:10.1055/s-0038-1655729

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1997; 77(01): 014-020
DOI: 10.1055/s-0038-1655729

Clinical Studies

Schattauer GmbH Stuttgart

Two Distinct Novel Splice Site Mutations in a Compound Heterozygous Patient with Protein S Deficiency

Tomio Yamazaki

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

,

Akira Katsumi

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

,

Yoshihiro Okamoto

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

²The Department of Clinical Pharmacy, Faculty of Pharmacy, Meijo University, Nagoya

,

Toshio Takafuta

³The Department of Hematology and Oncology, Division of Clinical Research, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

,

Shinobu Tsuzuki

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

,

Kazuo Kagami

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

,

Isamu Sugiura

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

,

Tetsuhito Kojima

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

,

Kingo Fujimura

³The Department of Hematology and Oncology, Division of Clinical Research, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

,

Hidehiko Saito

¹The First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya

› Author Affiliations

Abstract

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Summary

Genetic analysis revealed two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency. The paternal mutation was a G-to-T transition at position -1 of the acceptor splice site of intron N (Mutation I), and the maternal mutation was a G-to-C transversion at position -1 of the donor splice site of intron C (Mutation II). Both splice site mutations decreased the mutated mRNA accumulation to the same extent, approximately 40% of the normal mRNA. However, the mutations were associated with different phenotypical expressions: the paternal mutant protein S was not detected in vivo, while the maternal mutant protein S was present in the plasma in reduced quantity. Because Mutation I caused a cryptic splicing in the mutated mRNA, resulting in a reading frameshift and premature termination, the predicted mutant protein S might be highly unstable. In contrast, Mutation II led to the substitution of Val46 by Leu, which might be much less deleterious for the synthesis, secretion and stability of the predicted mutant protein S. It was supposed that the different post-translational metabolisms produced the distinct phenotypical expressions of the mutations.

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References

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