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Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees
BACKGROUND AND OBJECTIVES: Cerebral 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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9747143/ https://www.ncbi.nlm.nih.gov/pubmed/36524103 http://dx.doi.org/10.1212/NXG.0000000000200044 |
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author | Yao, Tingyan Zhu, Junge Wu, Xiao Li, Xuying Fu, Yongjuan Wang, Yuan Wang, Zhanjun Xu, Fanci Lai, Hong He, Aini Teng, Lianghong Wang, Chaodong Song, Haiqing |
author_facet | Yao, Tingyan Zhu, Junge Wu, Xiao Li, Xuying Fu, Yongjuan Wang, Yuan Wang, Zhanjun Xu, Fanci Lai, Hong He, Aini Teng, Lianghong Wang, Chaodong Song, Haiqing |
author_sort | Yao, Tingyan |
collection | PubMed |
description | BACKGROUND AND OBJECTIVES: Cerebral 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 heterozygous HTRA1 mutations 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 heterozygous HTRA1 mutation. METHODS: Three 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. RESULTS: Three novel heterozygous HTRA1 mutations (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 heterozygous HTRA1 mutation 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. DISCUSSION: These findings broaden the mutational and clinical spectrum of heterozygous HTRA1-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. |
format | Online Article Text |
id | pubmed-9747143 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Wolters Kluwer |
record_format | MEDLINE/PubMed |
spelling | pubmed-97471432022-12-14 Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees Yao, Tingyan Zhu, Junge Wu, Xiao Li, Xuying Fu, Yongjuan Wang, Yuan Wang, Zhanjun Xu, Fanci Lai, Hong He, Aini Teng, Lianghong Wang, Chaodong Song, Haiqing Neurol Genet Research Article BACKGROUND AND OBJECTIVES: Cerebral 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 heterozygous HTRA1 mutations 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 heterozygous HTRA1 mutation. METHODS: Three 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. RESULTS: Three novel heterozygous HTRA1 mutations (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 heterozygous HTRA1 mutation 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. DISCUSSION: These findings broaden the mutational and clinical spectrum of heterozygous HTRA1-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. Wolters Kluwer 2022-12-05 /pmc/articles/PMC9747143/ /pubmed/36524103 http://dx.doi.org/10.1212/NXG.0000000000200044 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Research Article Yao, Tingyan Zhu, Junge Wu, Xiao Li, Xuying Fu, Yongjuan Wang, Yuan Wang, Zhanjun Xu, Fanci Lai, Hong He, Aini Teng, Lianghong Wang, Chaodong Song, Haiqing Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees |
title | Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees |
title_full | Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees |
title_fullStr | Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees |
title_full_unstemmed | Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees |
title_short | Heterozygous HTRA1 Mutations Cause Cerebral Small Vessel Diseases: Genetic, Clinical, and Pathologic Findings From 3 Chinese Pedigrees |
title_sort | heterozygous htra1 mutations cause cerebral small vessel diseases: genetic, clinical, and pathologic findings from 3 chinese pedigrees |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9747143/ https://www.ncbi.nlm.nih.gov/pubmed/36524103 http://dx.doi.org/10.1212/NXG.0000000000200044 |
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