Two Unique Mutations in HTRA1-Related Cerebral Small Vessel Disease in North America and Africa and Literature Review

Shang, Ty; Pinho, Marco da Cunha; Ray, Debarti; Khera, Alka

doi:10.1016/j.jstrokecerebrovasdis.2021.106029

Cited by 8 publications

(3 citation statements)

References 7 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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“…L3/LD is essential for enzyme activation, while the linker region contains two stacking sites (Y169 and F171) crucial for trimerization (Liu et al, 2020). Notably, mutations located in the linker region were associated with later onset of symptoms but a predisposition for stroke occurrence (Shang et al, 2021).…”

Section: Mutation Sitesmentioning

confidence: 99%

Exploring HTRA1-Autosomal Dominant Disease: Literature Review of Clinical Features and Molecular Mechanisms

Li,

Zhu,

Yao

2023

Human Brain

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Heterozygous HTRA1-autosomal dominant disease is a gradually recognized hereditary cerebral small vessel disease (cSVD) characterized by debilitating conditions and extensive white matter hyperintensities (WMHs), but doubts remain on the underlying mechanisms of this disease. This review summarizes the clinical, MRI, and molecular genetics features of heterozygous HTRA1-autosomal dominant disease in combination with two better-studied hereditary cSVDs. A total of 31 mutations in HTRA1-autosomal dominant cases documented between 2020 and 2023 were also reviewed, characterizing the mutation features and clinical manifestations. This review aims to gain better insight into the unique characteristics of the disease and its correlations with other hereditary cSVDs.

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“…3,4 CARASIL is initially and most commonly reported in Japan, 1,2,5 and subsequently, some sporadic cases were identified worldwide, including China, India, the United States, Italy, and Spain. [5][6][7] CARASIL is extremely rare, with only 28 families reported to date. 8 However, recently, increasing reports have shown that heterozygous HTRA1 mutations are also associated with CSVD, showing that heterozygous HTRA1 mutations account for 0.8%-6.5% of CSVD cases without a NOTCH3 mutation worldwide.…”

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confidence: 99%

Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases

et al. 2022

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Background and ObjectivesCerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebrovascular disease caused by homozygous or compound heterozygous variations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. However, several studies in recent years have found that some heterozygousHTRA1mutations also cause cerebral small vessel disease (CSVD). The current study aims to report the novel genotypes, phenotypes, and histopathologic results of 3 pedigrees of CSVD with heterozygousHTRA1mutation.MethodsThree pedigrees of familiar CSVD, including 11 symptomatic patients and 3 asymptomatic carriers, were enrolled. Whole-exome sequencing was conducted in the probands for identifying rare variants, which were then evaluated for pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was performed for validation of mutations in the probands and other family members. The protease activity was assayed for the novel mutations. All the participants received detailed clinical and imaging examinations and the corresponding results were concluded. Hematoma evacuation was performed for an intracerebral hemorrhage patient with the p.Q318H mutation, and the postoperative pathology including hematoma and cerebral small vessels were examined.ResultsThree novel heterozygousHTRA1mutations (p.Q318H, p.V279M, and p.R274W) were detected in the 3 pedigrees. The protease activity was largely lost for all the mutations, confirming that they were loss-of-function mutations. The patients in each pedigree presented with typical clinical and imaging features of CVSD, and some of them displayed several new phenotypes including color blindness, hydrocephalus, and multiple arachnoid cysts. In addition, family 1 is the largest pedigree with heterozygousHTRA1mutation so far and includes homozygous twins, displaying some variation in clinical phenotypes. More importantly, pathologic study of a patient with p.Q318H mutation showed hyalinization, luminal stenosis, loss of smooth muscle cells, splitting of the internal elastic lamina, and intramural hemorrhage/dissection-like structures.DiscussionThese findings broaden the mutational and clinical spectrum of heterozygousHTRA1-related CSVD. Pathologic features were similar with the previous heterozygous and homozygous cases. Moreover, clinical heterogeneity was revealed within the largest single family, and the mechanisms of the phenotypic heterogenetic remain unclear. Overall, heterozygous HTRA1-related CSVD should not be simply taken as a mild type of CARASIL as previously considered.

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Two Unique Mutations in HTRA1-Related Cerebral Small Vessel Disease in North America and Africa and Literature Review

Cited by 8 publications

References 7 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

Exploring HTRA1-Autosomal Dominant Disease: Literature Review of Clinical Features and Molecular Mechanisms

Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases

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