Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease
Association of HTRA1 Mutations and Familial Ischemic Cerebral Small-Vessel Disease
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DOI：
10.1056/nejmoa0801560
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发表时间：
2009-04-23
影响因子：
158.5
通讯作者：
Onodera, Osamu
中科院分区：
文献类型：
--
作者：
Hara, Kenju;Shiga, Atsushi;Onodera, Osamu
背景常染色体隐性遗传性脑动脉病伴皮质下梗死和白质脑病（CARASIL）的遗传学病因尚不清楚，CARASIL以缺血性、非高血压性、脑小血管疾病伴脱发和颈椎病为特征，在5个CARASIL家系中，我们进行了连锁分析、精细定位与疾病有关的区域，并对候选基因进行了序列分析。我们还对野生型和突变基因产物进行了功能分析，并测量了转化生长因子β（TGF-β）家族成员的信号传导以及两名CARASIL患者大脑小动脉中的基因和蛋白表达。我们发现该疾病与染色体10 q上的2.4 Mb区域相关，该区域包含HtrA丝氨酸蛋白酶1（HTRA 1）基因。HTRA 1是一种丝氨酸蛋白酶，抑制TGF-β家族成员的信号传导。序列分析发现HTRA 1基因存在两个无义突变和两个错义突变。错义突变和其中一个无义突变导致蛋白质产物具有相对低水平的蛋白酶活性，并且不抑制TGF-β家族的信号传导。另一个无义突变通过无义介导的信使RNA衰变导致HTRA 1蛋白的丢失。受影响的人的大脑小动脉的免疫组织化学分析表明，在增厚的图尼卡内膜和TGF-β 1的图尼卡media.CONCLUSIONSCARASIL与HTRA 1基因突变的额外的结构域-A区的纤维连接蛋白和多功能蛋白聚糖的表达增加。我们的研究结果表明，TGF-β家族对信号传导的抑制与缺血性脑小血管疾病、脱发和颈椎病之间存在联系。
BACKGROUNDThe 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.METHODSIn 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.RESULTSWe 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.CONCLUSIONSCARASIL 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.