Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease
Abstract Objective ITPR3, encoding inositol 1,4,5‐trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot‐Marie‐Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot‐Marie‐Tooth disease gene. Methods Whole‐exome se...
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doaj-b677654436f5422098c6dce97f6fade52021-05-03T01:28:45ZengWileyAnnals of Clinical and Translational Neurology2328-95032020-10-017101962197210.1002/acn3.51190Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth diseaseJulius Rönkkö0Svetlana Molchanova1Anya Revah‐Politi2Elaine M. Pereira3Mari Auranen4Jussi Toppila5Jouni Kvist6Anastasia Ludwig7Julika Neumann8Geert Bultynck9Stéphanie Humblet‐Baron10Adrian Liston11Anders Paetau12Claudio Rivera13Matthew B. Harms14Henna Tyynismaa15Emil Ylikallio16Stem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki FinlandStem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki FinlandInstitute for Genomic Medicine Columbia University Medical Center New York New York USADepartment of Pediatrics Columbia University Irving Medical Center New York New York USAClinical Neurosciences Neurology University of Helsinki and Helsinki University Hospital Helsinki FinlandDepartment of Clinical Neurophysiology Medical Imaging Center Helsinki University Central Hospital Helsinki FinlandStem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki FinlandNeuroscience Center Helsinki Institute of Life Science University of Helsinki Helsinki FinlandDepartment of Microbiology and Immunology Laboratory of Adaptive Immunity KU Leuven Leuven BelgiumLaboratory of Molecular and Cellular Signaling Department of Cellular and Molecular Medicine & Leuven Kanker Instituut KU Leuven Leuven BelgiumVIB‐KU Leuven Center for Brain and Disease Research Leuven BelgiumDepartment of Microbiology and Immunology Laboratory of Adaptive Immunity KU Leuven Leuven BelgiumDepartment of Pathology HUSLAB and University of Helsinki Helsinki FinlandNeuroscience Center Helsinki Institute of Life Science University of Helsinki Helsinki FinlandDepartment of Neurology Columbia University New York New York USAStem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki FinlandStem Cells and Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki FinlandAbstract Objective ITPR3, encoding inositol 1,4,5‐trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot‐Marie‐Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot‐Marie‐Tooth disease gene. Methods Whole‐exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease‐causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging. Results Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+‐transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant‐negative effect on inositol 1,4,5‐trisphosphate receptor type 3 function. Interpretation Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease‐causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis.https://doi.org/10.1002/acn3.51190 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julius Rönkkö Svetlana Molchanova Anya Revah‐Politi Elaine M. Pereira Mari Auranen Jussi Toppila Jouni Kvist Anastasia Ludwig Julika Neumann Geert Bultynck Stéphanie Humblet‐Baron Adrian Liston Anders Paetau Claudio Rivera Matthew B. Harms Henna Tyynismaa Emil Ylikallio |
spellingShingle |
Julius Rönkkö Svetlana Molchanova Anya Revah‐Politi Elaine M. Pereira Mari Auranen Jussi Toppila Jouni Kvist Anastasia Ludwig Julika Neumann Geert Bultynck Stéphanie Humblet‐Baron Adrian Liston Anders Paetau Claudio Rivera Matthew B. Harms Henna Tyynismaa Emil Ylikallio Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease Annals of Clinical and Translational Neurology |
author_facet |
Julius Rönkkö Svetlana Molchanova Anya Revah‐Politi Elaine M. Pereira Mari Auranen Jussi Toppila Jouni Kvist Anastasia Ludwig Julika Neumann Geert Bultynck Stéphanie Humblet‐Baron Adrian Liston Anders Paetau Claudio Rivera Matthew B. Harms Henna Tyynismaa Emil Ylikallio |
author_sort |
Julius Rönkkö |
title |
Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease |
title_short |
Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease |
title_full |
Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease |
title_fullStr |
Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease |
title_full_unstemmed |
Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease |
title_sort |
dominant mutations in itpr3 cause charcot‐marie‐tooth disease |
publisher |
Wiley |
series |
Annals of Clinical and Translational Neurology |
issn |
2328-9503 |
publishDate |
2020-10-01 |
description |
Abstract Objective ITPR3, encoding inositol 1,4,5‐trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot‐Marie‐Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot‐Marie‐Tooth disease gene. Methods Whole‐exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease‐causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging. Results Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+‐transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant‐negative effect on inositol 1,4,5‐trisphosphate receptor type 3 function. Interpretation Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease‐causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis. |
url |
https://doi.org/10.1002/acn3.51190 |
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