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Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1.

ABSTRACT: Homozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a very rare hereditary cerebral small-vessel disease (SVD). Recently, the relationship between some heterozygous HTRA1 mutations, most of which are missense, and the occurrence of cerebral SVD has been reported. We herein report a patient with cerebral SVD carrying a heterozygous nonsense p.R302X mutation in HTRA1. This patient had a family history of cerebral infarction. This report suggests that a heterozygous p.R302X mutation in HTRA1 causes an autosomal dominant cerebral SVD.

SUBMITTER: Ohta K

PROVIDER: S-EPMC7303461 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1.

Ohta Kentaro K Ozawa Tetsuo T Fujinaka Hidehiko H Goto Kiyoe K Nakajima Takashi T

Internal medicine (Tokyo, Japan) 20200226 10

Homozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a very rare hereditary cerebral small-vessel disease (SVD). Recently, the relationship between some heterozygous HTRA1 mutations, most of which are missense, and the occurrence of cerebral SVD has been reported. We herein report a patient with cerebral SVD carrying a heterozygous nonse ...[more]

PMID: 32101834

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Project description:BackgroundHomozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 (HTRA1) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD.MethodsWe presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1-related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL.ResultsForty-four HTRA1-related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1-related autosomal dominant probands has a higher proportion of vascular risk factors (P < 0.001), a later onset age (P < 0.001), and a relatively slower clinical progression. Alopecia and spondylosis can be observed, but less than those in the typical CARASIL. Thirty-five heterozygous mutations in HTRA1 were reported, most of which were missense mutations. Amino acids located close to amino acids 250-300 were most frequently affected, followed by these located near 150∼200. While amino acids 250∼300 were also the most frequently affected region in CARASIL patients, fewer mutations precede the 200th amino acids were detected, especially in the Kazal-type serine protease domain.ConclusionsHTRA1-related autosomal dominant CSVD is present as a mild phenotype of CARASIL. The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1-related autosomal dominant CSVD.

Project description:Background: Homozygous and compound heterozygous mutations in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, heterozygous pathogenic variants in HTRA1 were described in patients with autosomal dominant cerebral small vessel disease (CSVD). Here, we investigated the genetic variants in a cohort of Chinese patients with CSVD. Methods: A total of 95 Chinese index patients with typical characteristics of CSVD were collected. Whole exome sequencing was performed in the probands, followed by Sanger sequencing. Pathogenicity prediction software was applied to evaluate the pathogenicity of the identified variants. Results: We detected five heterozygous HTRA1 pathogenic variants in five index patients. These pathogenic variants included four known variants (c.543delT, c.854C>T, c.889G>A, and c.824C>T) and one novel variant (c.472 + 1G>A). Among them, c.854C>T, c.824C>T, and c.472 + 1G>A have never been reported in China and c.889G>A was once reported in homozygous but never in heterozygous. Three of them were distributed in exon 4, one in exon 2, and another splicing variant in intron 1. Four out of five probands presented typical features of CARASIL but less severe. The common clinical features included lacunar infarction, cognitive decline, alopecia, and spondylosis. All of them showed leukoencephalopathy, and the main involved cerebral area include periventricular and frontal area, centrum semiovale, thalamus, and corpus callosum. Anterior temporal lobes and external capsule involvement were also observed. Three probands had intracranial microbleeds. Conclusion: Our study expanded the mutation spectrum of HTRA1, especially in Chinese populations, and provided further evidence for "hot regions" in exon 1-4, especially in exon 4, in heterozygous HTRA1 pathogenic variants. Our work further supported that patients with heterozygous HTRA1 pathogenic variants presented with similar but less-severe features than CARASIL but in an autosomal dominantly inherited pattern.

Project description:Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

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Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1.

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Cerebral Small Vessel Disease Related to a Heterozygous Nonsense Mutation in HTRA1.

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