A novel heterozygous HTRA1 mutation is associated with autosomal dominant hereditary cerebral small vessel disease

Zhuo, Zhongling; Cong, Lu; Zhang, Jun; Zhao, Xiaozheng

doi:10.1002/mgg3.1111

Cited by 7 publications

(7 citation statements)

References 26 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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“…The TGF-β binding protein, found in the extracellular matrix, is one of the HTRA1 proteolytic substrates. The reduced HTRA1 proteolytic activity due to pathogenic variants in the gene dysregulates the TGF-β signaling inhibition and leads to vasculopathy [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study

Grigaitė

Šiaurytė

Audronytė

et al. 2021

Genes

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Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient’s phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

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“…As for heterozygous HTRA1 gene variants, missense variants in p.R166L, 6 , 41 p.A173P, 6 , 41 p.V175M, 37 p.I256T, 30 p.F278L, 37 p.G283E, 20 , 41 p.S284R, 6 , 41 p.P285L, 20 , 37 p.G295R, 41 p. R302Q, 20 p.Q318H, 37 p.T319I, 20 p.V339M 37 and p.G350E 37 have dominant negative effects. However, missense variants in p.G120D, 30 p.R166C, 41 p.I179N, 30 p.S205C, 42 p.G276A, 30 p.P285Q, 6 , 41 p.F286V, 6 , 41 p.V297M 20 and p.N324T 30 do not show a dominant negative effect. Nonsense variant site p.Q289X may be submitted to nonsense mediated mRNA decay (NMD).…”

Section: Introductionmentioning

confidence: 92%

“… 44 The p.S205C variant site can upregulate the expression of TGF-β1, Smad2/3, Smad4, phosphorylated Smad2/3, and Smad4. 42 The abnormal signal transduction of the TGF-β1/Smads pathway may be a potential molecular pathogenic mechanism, suggesting that TGF-β1 antagonists can be used for the treatment of symptomatic heterozygous HTRA1 variant carriers. 42 In addition to the TGF-β1/Smad signaling pathway, a high expression of CTGF and PAI-1 genes was observed in patients with p.E42fs and p.A321T variants.…”

Section: Introductionmentioning

confidence: 99%

“… 42 The abnormal signal transduction of the TGF-β1/Smads pathway may be a potential molecular pathogenic mechanism, suggesting that TGF-β1 antagonists can be used for the treatment of symptomatic heterozygous HTRA1 variant carriers. 42 In addition to the TGF-β1/Smad signaling pathway, a high expression of CTGF and PAI-1 genes was observed in patients with p.E42fs and p.A321T variants. 39 It is suggested that the TGF-β1/non-Smad pathway may also be involved in the molecular pathogenesis of symptomatic heterozygous HTRA1 variant carriers.…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease

Xu¹,

Li²,

Li³

et al. 2023

IJGM

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High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166–182 aa and 274–302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.

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A novel heterozygous HTRA1 mutation is associated with autosomal dominant hereditary cerebral small vessel disease

Cited by 7 publications

References 26 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

Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study

Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease

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