Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease

被引：365

作者：

Hara, Kenju ^{[1
]}

Shiga, Atsushi ^{[1
]}

Fukutake, Toshio ^{[2
]}

Nozaki, Hiroaki ^{[1
]}

Miyashita, Akinori ^{[1
]}

Yokoseki, Akio ^{[1
]}

Kawata, Hirotoshi ^{[3
]}

Koyama, Akihide ^{[1
]}

Arima, Kunimasa ^{[4
]}

Takahashi, Toshiaki ^{[1
]}

Ikeda, Mari ^{[1
]}

Shiota, Hiroshi ^{[5
]}

Tamura, Masato ^{[6
]}

Shimoe, Yutaka ^{[7
]}

Hirayama, Mikio ^{[8
]}

Arisato, Takayo ^{[9
]}

Yanagawa, Sohei ^{[10
]}

Tanaka, Akira ^{[3
]}

Nakano, Imaharu ^{[3
]}

Ikeda, Shu-ichi ^{[11
]}

Yoshida, Yutaka ^{[1
]}

Yamamoto, Tadashi ^{[1
]}

Ikeuchi, Takeshi ^{[1
]}

Kuwano, Ryozo ^{[1
]}

Nishizawa, Masatoyo ^{[1
]}

Tsuji, Shoji ^{[12
]}

Onodera, Osamu ^{[1
]}

机构：

[1] Niigata Univ, Niigata, Japan

[2] Kameda Med Ctr, Kamogawa City, Chiba, Japan

[3] Jichi Med Univ, Shimotsuke, Tochigi, Japan

[4] Natl Ctr Neurol & Psychiat, Tokyo, Japan

[5] Nihon Univ, Sch Med, Tokyo, Japan

[6] Nagaoka Nishi Hosp, Nagaoka, Niigata, Japan

[7] Kashima Rosai Hosp, Kashima, Japan

[8] Kasugai Municipal Hosp, Kasugai, Aichi, Japan

[9] Minamikyushu Natl Hosp, Kagoshima, Japan

[10] Iida Municipal Hosp, Iida, Japan

[11] Shinshu Univ, Sch Med, Matsumoto, Nagano 390, Japan

[12] Univ Tokyo, Tokyo, Japan

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2009年 / 360卷 / 17期

基金：

日本学术振兴会;

关键词：

SMOOTH-MUSCLE-CELLS; AUTOSOMAL RECESSIVE ARTERIOPATHY; BONE MORPHOGENETIC PROTEINS; SERINE-PROTEASE HTRA1; GROWTH-FACTOR; MACULAR DEGENERATION; EXTRACELLULAR-MATRIX; SUBCORTICAL INFARCTS; BETA; EXPRESSION;

D O I：

10.1056/NEJMoa0801560

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, non-hypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear. METHODS In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL. RESULTS We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta 1 in the tunica media. CONCLUSIONS CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

引用

页码：1729 / 1739

页数：11

共 39 条

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