A missense
            <i>HTRA1</i>
            mutation expands CARASIL syndrome to the Caucasian population

Mendioroz, Maite; Fernández‐Cadenas, Israel; Río-Espínola, Alberto Del; Rovira, Ana; Solé, Elisabet; Fernández‐Figueras, María‐Teresa; García‐Patos, Vicente; Sastre‐Garriga, Jaume; Domingues‐Montanari, Sophie; Álvarez-Sabín, José; Montaner, Joan

doi:10.1212/wnl.0b013e3181ff96ac

Cited by 65 publications

(55 citation statements)

References 6 publications

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“…12 This mutation was predicted to be probably damaging by Polyphen-2 software. 15 The modelling results showed that the novel mutation (p.P285L) in the HTRA1 protein may attenuate the hydrogen bond between S284 and S287 residues.…”

Section: Discussionmentioning

confidence: 99%

“…CARASIL was diagnosed according to previously described criteria, including early adulthood onset of subcortical infarcts, alopecia, spondylosis and progressive cognitive impairment. [1][2][3][12][13][14] Healthy control subjects (50% male) were recruited from outpatient clinics at The First Affiliated Hospital of China Medical University between December 2010 and July 2012. Members of the CARASIL pedigree and control subjects were all of Chinese ancestry and came from China.…”

Section: Study Participantsmentioning

confidence: 99%

“…2,[6][7][8][9][10][11] CARASIL has been associated with mutations in the HTRA1 gene in several families. 2,[12][13][14] Seven mutations (p.A252T, p.R274Q, p.G295R, p.V297M, p.R302X, p.R370X and p.L364P) have been identified in exons 3, 4 and 6 of the HTRA1 gene in patients with CARASIL. 2,[12][13][14] The first novel mutation to be found in a Chinese pedigree was c.1091 T 4 C (p.L364P) in exon 6 of the HTRA1 gene; however, no further mutations have been confirmed in Chinese patients with CARASIL.…”

Section: Introductionmentioning

confidence: 99%

“…2,[12][13][14] Seven mutations (p.A252T, p.R274Q, p.G295R, p.V297M, p.R302X, p.R370X and p.L364P) have been identified in exons 3, 4 and 6 of the HTRA1 gene in patients with CARASIL. 2,[12][13][14] The first novel mutation to be found in a Chinese pedigree was c.1091 T 4 C (p.L364P) in exon 6 of the HTRA1 gene; however, no further mutations have been confirmed in Chinese patients with CARASIL. 14 The present study assessed the clinical and molecular genetic characteristics of a Chinese family with CARASIL to reveal the genetic causes of CARASIL in this family, and assess the role of HTRA1 gene mutations in its pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Chen

et al. 2013

J Int Med Res

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Objective: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene were studied in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Methods: Exons 1-9 of the HTRA1 gene were amplified and bidirectionally sequenced in a Chinese family with CARASIL. Mutation effects were analysed by three-dimensional modelling of the serine protease HTRA1 protein.Results: The proband was found to be homozygous for a novel missense mutation (c.854 C 4 T) identified in exon 4 of the HTRA1 gene; the parents of the proband were heterozygous for the same missense mutation. This c.854 C 4 T mutation resulted in a change from proline to leucine (p.P285L) in serine protease HTRA1, and was absent in 260 control chromosomes. Threedimensional models showed that the change from proline to leucine (p.P285L) could attenuate the hydrogen bond between S284 and S287 residues, which might affect function of serine protease HTRA1. Conclusion: Discovery of a novel missense mutation (c.854C>T) associated with CARASIL expands the known CARASIL-related mutations in HTRA1.

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Section: Discussionmentioning

confidence: 99%

Section: Study Participantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Chen

et al. 2013

J Int Med Res

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“…Initially thought to be restricted to the Japanese population, in recent years an increasing number of CARASIL cases has been reported from outside Japan indicating a more widespread distribution of this disorder. [33][34][35] The COL4A1/A2-related angiopathies (OMIM: 607595; 614519) represent highly penetrant multisystem disorders with heterogeneous phenotypes. 36 Heterozygous mutations in COL4A1 encoding the 1 chain of type IV procollagen were initially identified as a cause for porencephaly, an infantile neurologic disorder associated with hemorrhages and hemiplegia.…”

Section: Mendelian Forms Of Small Vessel Diseasementioning

confidence: 99%

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Haffner

Malik

Dichgans

2015

J Cereb Blood Flow Metab

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Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

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Rare neurovascular genetic and imaging markers across neurodegenerative diseases

Dilliott

Berberian

Sunderland

et al. 2023

Alzheimer's & Dementia

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IntroductionCerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)‐based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status.MethodsThe Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non‐synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1).ResultsNOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood.DiscussionFurther studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases.

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A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population

Cited by 65 publications

References 6 publications

A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

A novel mutation of the high-temperature requirement A serine peptidase 1 (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Rare neurovascular genetic and imaging markers across neurodegenerative diseases

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