HeterozygousHTRA1mutations are associated with autosomal dominant cerebral small vessel disease

Abstract

Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology.

Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease

“…We point out the limitation of our study consisting in the absence of functional studies, although functional studies on the HTRA1 mutant protein does not necessarily resolve the question regarding the pathogenicity: Verdura et al . show a complete loss of protease activity only in five of seven pathogenic variants described, and Nozaki et al .…”

“…Herein, we reported clinical, MRI, and genetic details of nine individuals from five unrelated families with familial cerebral SVD related to heterozygous mutations of HTRA1 gene. The pathogenic role in late‐onset cerebrovascular phenotype of heterozygous HTRA1 gene mutations, otherwise causative in homozygosity of CARASIL, was recently hypothesized by Verdura et al …”

Cerebrovascular disorders associated with genetic lesions

“…Histological findings include intense atherosclerosis affecting mainly small penetrating arteries; GOM or amyloid deposits are however absent. Biallelic mutations in HTRA1 , encoding a serine protease implicated in negative regulation of TGFβ signaling, have been associated with CARASIL [183, 232]; interestingly, heterozygous HTRA1 mutations have also been reported in a family with autosomal dominant SVD with clinical features distinct from CARASIL and CADASIL [233]. …”

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

“…3,4 In these patients, mutated HTRA1 has decreased protease activity or inhibits wild-type HTRA1 activity. 3,4 In these patients, mutated HTRA1 has decreased protease activity or inhibits wild-type HTRA1 activity.…”