Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease.
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Authors
Molchanova, Svetlana
Revah-Politi, Anya
Pereira, Elaine M
Auranen, Mari
Toppila, Jussi
Kvist, Jouni
Ludwig, Anastasia
Neumann, Julika
Bultynck, Geert
Humblet-Baron, Stéphanie
Paetau, Anders
Rivera, Claudio
Harms, Matthew B
Tyynismaa, Henna
Publication Date
2020-10Journal Title
Ann Clin Transl Neurol
ISSN
2328-9503
Publisher
Wiley
Volume
7
Issue
10
Pages
1962-1972
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Rönkkö, J., Molchanova, S., Revah-Politi, A., Pereira, E. M., Auranen, M., Toppila, J., Kvist, J., et al. (2020). Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease.. Ann Clin Transl Neurol, 7 (10), 1962-1972. https://doi.org/10.1002/acn3.51190
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.
Keywords
Humans, Arthrogryposis, Charcot-Marie-Tooth Disease, Pedigree, Heterozygote, Genes, Recessive, Phenotype, Mutation, Adult, Aged, Middle Aged, Inositol 1,4,5-Trisphosphate Receptors, Young Adult
Identifiers
External DOI: https://doi.org/10.1002/acn3.51190
This record's URL: https://www.repository.cam.ac.uk/handle/1810/312889
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