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Previous Volume 360:1729-1739 April 23, 2009 Number 17 Next

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ABSTRACT

Background The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, nonhypertensive, 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 β (TGF-β) 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-β 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-β 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-β1 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-β family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

Source Information

From Niigata University, Niigata (K.H., A.S., H.N., A.M., A.Y., A.K., T.T., M.I., Y.Y., T.Y., T.I., R.K., M.N., O.O.); Kameda Medical Center, Kamogawa City (T.F.); Jichi Medical University, Tochigi (H.K., A.T., I.N.); National Center of Neurology and Psychiatry, Tokyo (K.A.); Nihon University School of Medicine, Tokyo (H.S.); Nagaoka-Nishi Hospital, Nagaoka (M.T.); Kashima Rosai Hospital, Kashima (Y.S.); Kasugai Municipal Hospital, Kasugai (M.H.); Minamikyushu National Hospital, Kagoshima (T.A.); Iida Municipal Hospital, Iida (S.Y.); Shinshu University School of Medicine, Matsumoto (S.I.); and University of Tokyo, Tokyo (S.T.) — all in Japan.

Dr. Hara and Mr. Shiga contributed equally to this article.

Address reprint requests to Dr. Onodera at the Brain Research Institute, Niigata 951-8585, Japan, or at onodera{at}bri.niigata-u.ac.jp.

Full Text of this Article

This article has been cited by other articles:

• (2009). Genetic Basis of an Autosomal Recessive Small-Vessel Disease of the Brain. JWatch Neurology 2009: 3-3 [Full Text]