title: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.
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 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-beta1 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.
authors.affiliation: Niigata University, Niigata, Japan.
authors.forename: Kenju
authors.initials: K
authors.lastname: Hara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukutake
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozaki
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kawata
authors.forename: Akihide
authors.initials: A
authors.lastname: Koyama
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Arima
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Mari
authors.initials: M
authors.lastname: Ikeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiota
authors.forename: Masato
authors.initials: M
authors.lastname: Tamura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimoe
authors.forename: Mikio
authors.initials: M
authors.lastname: Hirayama
authors.forename: Takayo
authors.initials: T
authors.lastname: Arisato
authors.forename: Sohei
authors.initials: S
authors.lastname: Yanagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Ikeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000505:Alopecia / Q000235:genetics*; D002539:Cerebral Arterial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002536:Cerebral Arteries / Q000473:pathology; D002544:Cerebral Infarction / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction; D055009:Spondylosis / Q000235:genetics*; D013577:Syndrome; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000473:pathology
chemical_list: D016212:Transforming Growth Factor beta; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases