Premium
A Mitochondrial tRNA Mutation Causes Axonal CMT in a Large Venezuelan Family
Author(s) -
Fay Alexander,
Garcia Yngo,
Margeta Marta,
Maharjan Sunita,
Jürgensen Claudia,
Briceño Jose,
Garcia Mariaelena,
Yin Sitao,
Bassaganyas Laia,
McMahon Thomas,
Hou YaMing,
Fu YingHui,
Ptáček Louis J.
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25854
Subject(s) - heteroplasmy , mitochondrial dna , biology , mitochondrial disease , genetics , transfer rna , mitochondrion , mutation , gene , microbiology and biotechnology , rna
Objective The objective of this study was to identify the genetic cause for progressive peripheral nerve disease in a Venezuelan family. Despite the growing list of genes associated with Charcot‐Marie‐Tooth disease, many patients with axonal forms lack a genetic diagnosis. Methods A pedigree was constructed, based on family clinical data. Next‐generation sequencing of mitochondrial DNA (mtDNA) was performed for 6 affected family members. Muscle biopsies from 4 family members were used for analysis of muscle histology and ultrastructure, mtDNA sequencing, and RNA quantification. Ultrastructural studies were performed on sensory nerve biopsies from 2 affected family members. Results Electrodiagnostic testing showed a motor and sensory axonal polyneuropathy. Pedigree analysis revealed inheritance only through the maternal line, consistent with mitochondrial transmission. Sequencing of mtDNA identified a mutation in the mitochondrial tRNA Val ( mt‐tRNA Val ) gene, m.1661A>G, present at nearly 100% heteroplasmy, which disrupts a Watson–Crick base pair in the T‐stem‐loop. Muscle biopsies showed chronic denervation/reinnervation changes, whereas biochemical analysis of electron transport chain (ETC) enzyme activities showed reduction in multiple ETC complexes. Northern blots from skeletal muscle total RNA showed severe reduction in abundance of mt‐tRNA Val , and mildly increased mt‐tRNA Phe , in subjects compared with unrelated age‐ and sex‐matched controls. Nerve biopsies from 2 affected family members demonstrated ultrastructural mitochondrial abnormalities (hyperplasia, hypertrophy, and crystalline arrays) consistent with a mitochondrial neuropathy. Conclusion We identify a previously unreported cause of Charcot‐Marie‐Tooth (CMT) disease, a mutation in the mt‐tRNA Val , in a Venezuelan family. This work expands the list of CMT‐associated genes from protein‐coding genes to a mitochondrial tRNA gene. ANN NEUROL 2020;88:830–842