A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

Han, Guoqing; Ma, Li; Qiao, Hui; Lin, Han; Wu, Qiaoli; Li, Qingguo

doi:10.3389/fnins.2020.604350

Cited by 4 publications

(6 citation statements)

References 30 publications

(40 reference statements)

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“…A retrieved result from Web of Science, PubMed, and Wanfang Data Knowledge Service Platform databases since 2000, with the terms familial cerebral cavernous malformations, mutation, and Chinese, articles published in English or Chinese with essential information about the mutations were included. We collected 24 pathogenetic alterations of fCCMs first identified in the Chinese population ( Chen et al, 2002 ; Xu et al, 2003 ; Mao et al, 2005 , 2016 ; Ji et al, 2006 ; Zhao et al, 2011 ; Wang et al, 2013 , 2017 , 2018 ; Zhu et al, 2014 ; Yang et al, 2017 ; Du et al, 2019 ; Han et al, 2020 ; Jiang et al, 2020 ; Yang L. et al, 2020 ; Yang Q. et al, 2020 ; Zhang et al, 2020 ; Liu et al, 2022 ). As exhibited in Table 3 , the majority (18/24) of Chinese fCCMs pathogenetic alterations are in KRIT1/CCM1 gene.…”

Section: Resultsmentioning

confidence: 99%

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Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view

et al. 2023

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Cerebral cavernous malformations (CCMs) are common vascular anomaly diseases in the central nervous system associated with seizures, cerebral microbleeds, or asymptomatic mostly. CCMs can be classified as sporadic or familial, with familial cerebral cavernous malformations (fCCMs) being the autosomal dominant manner with incomplete penetrance. Germline mutations of KRIT1, CCM2, and PDCD10 are associated with the pathogenesis of fCCMs. Till now, little is known about the fCCMs mutation spectrum in the Han Chinese population. In this study, we enrolled a large, aggregated family, 11/26 of the family members were diagnosed with CCMs by pathological or neuroradiological examination, with a high percentage (5/9) of focal spinal cord involvement. Genomic DNA sequencing verified a novel duplication mutation (c.1119dupT, p.L374Sfs*9) in exon 9 of the Krev interaction trapped 1 (KRIT1) gene. The mutation causes a frameshift and is predicted to generate a truncated KRIT1/CCM1 protein of 381 amino acids. All our findings confirm that c.1119dupT mutation of KRIT1 is associated with fCCMs, which enriched the CCM genes’ mutational spectrum in the Chinese population and will be beneficial for deep insight into the pathogenesis of Chinese fCCMs. Additionally, with a retrospective study, we analyzed the molecular genetic features of Chinese fCCMs, most of the Chinese fCCMs variants are in the KRIT1 gene, and all these variants result in the functional deletion or insufficiency of the C-terminal FERM domain of the KRIT1 protein.

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Section: Resultsmentioning

confidence: 99%

“…The genomic DNA was extracted from each family member’s peripheral blood. DNA libraries were constructed and sequenced to a target depth of 100 × on the Illumina X-TEN platform, as previously reported ( Han et al, 2020 ). Reads were aligned to the reference genome (hg19) using BWA-MEM.…”

Section: Methodsmentioning

confidence: 99%

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view

et al. 2023

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“…Although this work was primarily focused on the traditionally recognized PTB functional pocket, Core2, it provided the foundation for one of our protein structural simulation programs, probability density functions-based MODELLER [23], making our novel integrated in-silico/structural simulation analysis more thorough. Furthermore, recent efforts for in-silico analysis of Core1 in a genetic variant that is co-segregated in a large Chinese CCM pedigree [33] provide us with additional strong evidence for supporting this methodology. On the structural level, each amino acid substitution frequently resulted in perturbations within the tertiary structure of the PTB domain.…”

Section: Discussionmentioning

confidence: 96%

“…3, Supple Fig. 2A, Supple Video 3A, 3E) is a pathogenic mutation in the β2 strand (β-sheet 1), with minimal overlap between the amino acid side chains in both tertiary structure modalities [33]. There is misalignment in the β2, β2/3 loop, and α1/β2 loop between the two structures.…”

Section: Genomic Variants With Nssnps Only Have Local Effectsmentioning

confidence: 99%

In silico Analysis of Nonsynonymous Genomic Variants within CCM2 Gene Reaffirm the Existence of Dual Cores within Typical PTB Domain

Padarti

Belkin

Abou‐Fadel

et al. 2021

Preprint

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PurposeThe objective of this study is to validate the existence of dual cores within the typical phosphotyrosine binding (PTB) domain and to identify potentially damaging and pathogenic nonsynonymous coding single nuclear polymorphisms (nsSNPs) in the canonical PTB domain of the CCM2 gene that causes cerebral cavernous malformations (CCMs).MethodsThe nsSNPs within the coding sequence for PTB domain of human CCM2 gene, retrieved from exclusive database search, were analyzed for their functional and structural impact using a series of bioinformatic tools. The effects of the mutations on tertiary structure of the PTB domain in human CCM2 protein were predicted to examine the effect of the nsSNPs on tertiary structure on PTB Cores.ResultsOur mutation analysis, through alignment of protein structures between wildtype CCM2 and mutant, indicated that the structural impacts of pathogenic nsSNPs is biophysically limited to only the spatially adjacent substituted amino acid site with minimal structural influence on the adjacent core of the PTB domain, suggesting both cores are independently functional and essential for proper CCM2 function.ConclusionUtilizing a combination of protein conservation and structure-based analysis, we analyzed the structural effects of inherited pathogenic mutations within the CCM2 PTB domain. Our results indicated that the pathogenic amino acid substitutions lead to only subtle changes locally confined to the surrounding tertiary structure of the PTB core within which it resides, while no structural disturbance to the neighboring PTB core was observed, reaffirming the presence of dual functional cores in the PTB domain.

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“…A large autopsy study showed that the prevalence of CCM accounted for 0.1 to 0.5% of the total population ( 3 ), while other research has indicated that CCM influences ~10 to 20% of all cerebral vascular abnormalities ( 4 ). The disease can occur sporadically or by way of familial autosomal dominant inheritance without complete penetrance ( 5 ), with most cases having the former nature. The age of onset of CCM is typically 20 to 30 years of age or older.…”

Section: Introductionmentioning

confidence: 99%

A Chinese Family With Cerebral Cavernous Malformation Caused by a Frameshift Mutation of the CCM1 Gene: A Case Report and Review of the Literature

Liu

et al. 2022

Front. Neurol.

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BackgroundFamilial cerebral cavernous malformation (FCCM) is a vascular malformation disease closely linked to three identified genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Over the past decade, a few cases of cerebral cavernous malformation (CCM) caused by different gene mutations have been reported in Chinese families. Herein, we introduce a Chinese family affected by FCCM due to a kind of KRIT1/CCM1 frameshift mutation. At the same time, a literature review was conducted to identify case reports of familial cerebral cavernous malformation.Case presentationThe proband in the family in question demonstrated a series of clinical symptoms and features, including headache and bleeding. The proband was hospitalized for headache twice and, both times was examined under suspicion of CCM and received surgical treatment. Magnetic resonance imaging results showed that the proband had multiple intracranial vascular lesions, including on the brain, brainstem, and cerebellum. Genetic test results showed that the classic KRIT1 gene in the proband had a pathogenic mutation. The family members of the proband also showed typical cerebral cavernous malformation when considering clinical manifestations, magnetic resonance imaging findings and genetic test results.ConclusionsWe report a case of Chinese FCCM and its associated symptoms with CCM1-deletion mutations in China. Our findings deepen our understanding of CCM mutations and related phenotypes, the investigation results of this clinical experiment further show that the gene mutation form we reported plays an important role in human FCCM, and this trial investigation is beneficial for genetic counseling for CCM patients.

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A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

Cited by 4 publications

References 30 publications

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view

In silico Analysis of Nonsynonymous Genomic Variants within CCM2 Gene Reaffirm the Existence of Dual Cores within Typical PTB Domain

A Chinese Family With Cerebral Cavernous Malformation Caused by a Frameshift Mutation of the CCM1 Gene: A Case Report and Review of the Literature

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