A novel heterozygous <i>HTRA1</i> mutation in an Asian family with CADASIL‐like disease

Cao, Hua; Liu, Jiahui; Tian, Wen; Ji, Xiaofei; Wang, Qi; Luan, Siyu; Dong, Huijie

doi:10.1002/jcla.24174

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…Up to this study, there have been 40 single heterozygous HTRA1 mutations ( Figure 2 ) ( Verdura et al, 2015 ; Ihara, 2016 ; Nozaki et al, 2016 ; Bougea et al, 2017 ; Di Donato et al, 2017 ; Ito et al, 2018 ; Kono et al, 2018 ; Lee et al, 2018 ; Pati and Battisti, 2018 ; Thaler et al, 2018 ; Wu et al, 2018 ; Zhang et al, 2018 ; Favaretto et al, 2019 ; Liu et al, 2020 ; Ohta et al, 2020 ; Oluwole et al, 2020 ; Zhuo et al, 2020 ; Bekircan-Kurt et al, 2021 ; Grigaitė et al, 2021 ; Shang et al, 2021 ; Cao et al, 2022 ). In this study, we collected 95 Chinese CSVD patients and performed genetic analysis in the probands.…”

Section: Discussionmentioning

confidence: 96%

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 96%

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

et al. 2022

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“… 33 , 39 , 40 MRI of the head showed typical features of cerebral small-vessel disease, with pathological manifestations of intimal thickening, epicardial fibrosis, degeneration and loss of smooth muscle cells, and delamination and splitting of the internal elastic lamina of small vessels. 37 There were no osmiophilic granules on the surface of vascular smooth muscle on electron microscopy. It has been shown that mutations in the heterozygous HTRA1 gene result in a reduction in the protein hydrolysis activity of HTRA1, 41 which is accompanied by an increase in the levels of TGF-β1/Smad proteins, with a similar molecular mechanism to CARASIL.…”

Section: Htra1 Gene Abnormalities and Cerebrovascular Diseasementioning

confidence: 93%

“…Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be divided into 2 types, one is CADASIL type 1 (CADASIL1, OMIM 125310), caused by mutations in the NOTCH receptor 3 gene (NOTCH3), is the most common hereditary cerebral small vessel disease 35 and is broadly referred to collectively as CADASIL, while the other type, CADASIL type 2 (CADASIL2, OMIM 616779), also known as symptomatic carriers of HTRA1 gene mutations, 33 , 36 and studies have found that HTRA1 heterozygous mutations can cause cerebrovascular abnormalities. 37 The clinical manifestations of CARASIL and symptomatic carriers of HTRA1 mutations are approximately the same, but the latter have milder clinical symptoms 14 , 38 and later onset. 33 , 39 , 40 MRI of the head showed typical features of cerebral small-vessel disease, with pathological manifestations of intimal thickening, epicardial fibrosis, degeneration and loss of smooth muscle cells, and delamination and splitting of the internal elastic lamina of small vessels.…”

Section: Htra1 Gene Abnormalities and Cerebrovascular Diseasementioning

confidence: 99%

Progress in the Study of the Role and Mechanism of HTRA1 in Diseases Related to Vascular Abnormalities

Song,

Li,

Xue

et al. 2024

IJGM

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High temperature requirement A1 (HTRA1) is a member of the serine protease family, comprising four structural domains: IGFBP domain, Kazal domain, protease domain and PDZ domain. HTRA1 encodes a serine protease, a secreted protein that is widely expressed in the vasculature. HTRA1 regulates a wide range of physiological processes through its proteolytic activity, and is also involved in a variety of vascular abnormalities-related diseases. This article reviews the role of HTRA1 in the development of vascular abnormalities-related hereditary cerebral small vessel disease (CSVD), age-related macular degeneration (AMD), tumors and other diseases. Through relevant research advances to understand the role of HTRA1 in regulating signaling pathways or refolding, translocation, degradation of extracellular matrix (ECM) proteins, thus directly or indirectly regulating angiogenesis, vascular remodeling, and playing an important role in vascular homeostasis, further understanding the mechanism of HTRA1’s role in vascular abnormality-related diseases is important for HTRA1 to be used as a therapeutic target in related diseases.

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A novel heterozygous HTRA1 mutation in an Asian family with CADASIL‐like disease

Cao

Liu

Tian

et al. 2021

Clinical Laboratory Analysis

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Cerebral small vessel disease (CSVD) refers to lesions of the cerebral arterioles, venules, and capillaries caused by various causes. 1 Clinical manifestations of this type of disease are cognitive decline, abnormal gait, decreased executive function, mental symptoms, etc. 2 CSVD can be divided into sporadic and hereditary. Sporadic CSVD is mainly related to age, hypertension, diabetes, smoking, and other risk factors. 3 Hereditary CSVD accounts for approximately 5% of all cerebrovascular diseases caused by gene mutations, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive

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A novel heterozygous HTRA1 mutation in an Asian family with CADASIL‐like disease

Cited by 5 publications

References 15 publications

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

Progress in the Study of the Role and Mechanism of HTRA1 in Diseases Related to Vascular Abnormalities

A novel heterozygous HTRA1 mutation in an Asian family with CADASIL‐like disease

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