Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease

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Rönkkö , J , Molchanova , S , Revah-Politi , A , Pereira , E M , Auranen , M , Toppila , J , Kvist , J , Ludwig , A , Neumann , J , Bultynck , G , Humblet-Baron , S , Liston , A , Paetau , A , Rivera , C , Harms , M B , Tyynismaa , H & Ylikallio , E 2020 , ' Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease ' , Annals of Clinical and Translational Neurology , vol. 7 , no. 10 , pp. 1962-1972 .

Title: Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease
Author: Rönkkö, Julius; Molchanova, Svetlana; Revah-Politi, Anya; Pereira, Elaine M.; Auranen, Mari; Toppila, Jussi; Kvist, Jouni; Ludwig, Anastasia; Neumann, Julika; Bultynck, Geert; Humblet-Baron, Stephanie; Liston, Adrian; Paetau, Anders; Rivera, Claudio; Harms, Matthew B.; Tyynismaa, Henna; Ylikallio, Emil
Contributor organization: STEMM - Stem Cells and Metabolism Research Program
Faculty of Medicine
University of Helsinki
Research Programs Unit
Molecular and Integrative Biosciences Research Programme
Faculty of Biological and Environmental Sciences
HUS Neurocenter
Neurologian yksikkö
Department of Neurosciences
Helsinki University Hospital Area
HUS Medical Imaging Center
Department of Diagnostics and Therapeutics
Kliinisen neurofysiologian yksikkö
Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Department of Pathology
Centre of Excellence in Stem Cell Metabolism
Department of Medical and Clinical Genetics
Henna Tyynismaa / Principal Investigator
Basal ganglia circuits
Date: 2020-10
Language: eng
Number of pages: 11
Belongs to series: Annals of Clinical and Translational Neurology
ISSN: 2328-9503
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 thatITPR3is 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 Ca(2+)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 heterozygousITPR3p.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 ade novo ITPR3variant 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 thatITPR3is a disease-causing gene for CMT and indicates altered Ca(2+)homeostasis in disease pathogenesis.
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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