Rs2293871 regulates HTRA1 expression and affects cerebral small vessel stroke and Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Liu G
PROVIDER: S-EPMC6821345 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Rs2293871 regulates HTRA1 expression and affects cerebral small vessel stroke and Alzheimer's disease.
Liu Guiyou G Zhang Haihua H Liu Bian B Ji Xunming X
Brain : a journal of neurology 20191101 11
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Project description:Cerebral small vessel disease (CSVD) refers to a series of clinical, radiological, and pathological syndromes caused by various etiologies affecting small arteries, arterioles, venules, capillaries, and small veins in the brain. It can lead to cognitive impairment, stroke, gait abnormalities, and other neurological symptoms and signs. Globally, approximately 25% to 30% of strokes are caused by CSVD. The underlying mechanisms of CSVD are multifaceted, involving endothelial dysfunction, blood-brain barrier (BBB) inflammation, neuronal apoptosis, chronic cerebral hypoperfusion, and their complex interactions. Current treatments often fail to achieve satisfactory outcomes. Therefore, understanding the pathogenic mechanisms of CSVD is crucial for developing effective therapeutic strategies to mitigate its detrimental effects. The high-temperature requirement protease A-1 (HTRA1) mutations can cause hereditary CSVD. CSVD associated with HTRA1 mutations is referred to as HTRA1-associated CSVD. Homozygous HTRA1 mutations cause Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL), a rare hereditary CSVD that is inherited in an autosomal recessive manner. Heterozygous HTRA1 mutations can lead to Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy type 2 (CADASIL 2), also known as heterozygous HTRA1 mutation carriers. This condition is characterized by clinical manifestations such as stroke, cognitive impairment, gait abnormalities, alopecia, and spondylosis. To date, 35 pathogenic mutations in the HTRA1 gene have been reported, primarily exhibiting autosomal dominant inheritance. Current research mainly focuses on case reports and the potential pathogenic mechanisms associated with different mutation sites. HTRA1 mutations can lead to downregulation of HTRA1 mRNA and protein expression, thereby reducing HTRA1 protease activity. However, the specific morphological and functional changes associated with CSVD, especially those in endothelial cells, remain unclear. This study aims to explore the mutation spectrum and clinical phenotypes of heterozygous HTRA1 mutation carriers. By comparing whole-blood RNA sequencing (RNA-seq) analysis between heterozygous HTRA1 mutation carriers and healthy controls, we identify differentially expressed genes. Based on the RNA-seq results, we further investigate the effects of abnormal HtrA1 expression on the biological functions of mouse brain microvascular endothelial cells and mouse cognitive behavior. This study elucidates the role of HTRA1 in CSVD, providing insights into the pathogenesis and new therapeutic targets for patients with heterozygous HTRA1 mutations.
2026-03-11 | GSE324041 | GEO
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.
| S-EPMC7817319 | biostudies-literature
Project description:Cerebral small vessel disease (CSVD) is a group of pathological processes with multifarious etiology and pathogenesis that are involved into the small arteries, arterioles, venules, and capillaries of the brain. CSVD mainly contains lacunar infarct or lacunar stroke, leukoaraiosis, Binswanger's disease, and cerebral microbleeds. CSVD is an important cerebral microvascular pathogenesis as it is the cause of 20% of strokes worldwide and the most common cause of cognitive impairment and dementia, including vascular dementia and Alzheimer's disease (AD). It has been well identified that CSVD contributes to the occurrence of AD. It seems that the treatment and prevention for cerebrovascular diseases with statins have such a role in the same function for AD. So far, there is no strong evidence-based medicine to support the idea, although increasing basic studies supported the fact that the treatment and prevention for cerebrovascular diseases will benefit AD. Furthermore, there is still lack of evidence in clinical application involved in specific drugs to benefit both AD and CSVD.
| S-EPMC4629951 | biostudies-literature
Project description: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.
| S-EPMC7303461 | biostudies-literature
Project description: Not available
| S-EPMC11575887 | biostudies-literature
Project description:HTRA1 Mutation and Expression Regulation in Cerebral Small Vessel Disease
| PRJNA1433271 | ENA
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.
| S-EPMC9399615 | biostudies-literature
Project description:AimsCerebral small vessel disease (SVD) is the leading cause of vascular dementia. Although the most of cases are sporadic, familial monogenic causes have been identified in a growing minority of patients. CADASIL, due to mutations of NOTCH3 gene, is the most common genetic SVD, and CARASIL, linked to HTRA1 gene mutations, is a rare but well known autosomal recessive SVD. Recently, also heterozygous HTRA1 mutations have been described in patients with familial SVD. To detect a genetic cause of familial SVD, we performed mutational analysis of HTRA1 gene in a large cohort of Italian NOTCH3-negative patients.MethodsWe recruited 142 NOTCH3-negative patients and 160 healthy age-matched controls. Additional control data were obtained from five pathogenicity prediction software.ResultsFive different HTRA1 heterozygous mutations were detected in nine patients from five unrelated families. Clinical phenotype was typical of SVD, and the onset was presenile. Brain magnetic resonance imaging (MRI) showed a subcortical leukoencephalopathy, with involvement of the external and internal capsule, corpus callosum, and multiple lacunar infarcts. Cerebral microbleeds were also seen, while anterior temporal lobes involvement was not present.ConclusionOur observation further supports the pathogenic role of the heterozygous HTRA1 mutations in familial SVD.
| S-EPMC6492684 | biostudies-literature
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.
| S-EPMC7351529 | biostudies-literature
Project description:ObjectiveThere is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1-related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1-related CSVD, and we compared the features of heterozygous HTRA1-related CSVD and CADASIL.MethodsWe carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1-related CSVD and CADASIL were compared.ResultsWe identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1-related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001).InterpretationThis study shows that most HTRA1-related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra-neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1-related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.
| S-EPMC9539375 | biostudies-literature