Distinct molecular mechanisms of
            <i>HTRA1</i>
            mutants in manifesting heterozygotes with CARASIL

Nozaki, Hiroaki; Kato, Taisuke; Nihonmatsu, Megumi; Saito, Yohei; Mizuta, Ikuko; Noda, Tomoko; Koike, Ryoko; Miyazaki, Keisuke; Kaito, Muichi; Ito, Shingo; Makino, Masahiro; Koyama, Akira; Shiga, Atsushi; Uemura, Masahiro; Sekine, Yumi; Murakami, Ayuka; Moritani, Suzuko; Hara, Kenju; Yokoseki, Akio; Kuwano, Ryozo; Endo, Naoto; Momotsu, Takeshi; Yoshida, Mari; Nishizawa, Masatoyo; Mizuno, Toshiki; Onodera, Osamu

doi:10.1212/wnl.0000000000002694

Cited by 97 publications

(135 citation statements)

References 28 publications

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“…4 In comparison with that patient, the present one had apparently mild vascular changes and leukoencephalopathy. The first such patient reported, who had a p. G283E HTRA1 mutation, showed severe vascular changes and leukoencephalopathy.…”

Section: Discussioncontrasting

confidence: 39%

“…The first such patient reported, who had a p. G283E HTRA1 mutation, showed severe vascular changes and leukoencephalopathy. 4 Therefore, in the present patient, although a severe pathologic phenotype was expected, this was not the case. It has been shown that the protease activity can differ according to the mutation locus in HTRA1 1,4 and that the activity might correlate with the severity of the vascular changes and leukoencephalopathy.…”

Section: Discussionmentioning

confidence: 53%

“…3,4 In these patients, mutated HTRA1 has decreased protease activity or inhibits wild-type HTRA1 activity. 3,4 In these patients, mutated HTRA1 has decreased protease activity or inhibits wild-type HTRA1 activity.…”

Section: Introductionmentioning

confidence: 99%

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Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

et al. 2018

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

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Section: Discussioncontrasting

confidence: 39%

Section: Discussionmentioning

confidence: 53%

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Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

et al. 2018

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“…We point out the limitation of our study consisting in the absence of functional studies, although functional studies on the HTRA1 mutant protein does not necessarily resolve the question regarding the pathogenicity: Verdura et al . show a complete loss of protease activity only in five of seven pathogenic variants described, and Nozaki et al . present HTRA1 mutant with no reduction in protease activity.…”

Section: Discussionmentioning

confidence: 91%

“…Mild phenotypic expression in heterozygotes for recessive diseases has largely described for an increasing number of diseases . As regards to the pathogenic mechanism of heterozygous HTRA1 mutations, Nozaki et al . suggested a dominant‐negative effect.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease

et al. 2017

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Novel mutations in HTRA1‐related cerebral small vessel disease and comparison with CADASIL

Zhang

Zheng

et al. 2022

Ann Clin Transl Neurol

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Objective There is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1‐related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1‐related CSVD, and we compared the features of heterozygous HTRA1‐related CSVD and CADASIL. Methods We carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1‐related CSVD and CADASIL were compared. Results We identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1‐related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001). Interpretation This study shows that most HTRA1‐related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra‐neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1‐related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.

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Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL

Abstract: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

Cited by 97 publications

References 28 publications

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

Histopathologic features of an autopsied patient with cerebral small vessel disease and a heterozygous HTRA1 mutation

Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease

Novel mutations in HTRA1‐related cerebral small vessel disease and comparison with CADASIL

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