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Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy
- Source :
- Annals of Clinical and Translational Neurology, Annals of Clinical and Translational Neurology, Vol 6, Iss 9, Pp 1728-1738 (2019)
- Publication Year :
- 2019
- Publisher :
- John Wiley and Sons Inc., 2019.
-
Abstract
- Objective To identify a new genetic cause in patients segregating distal hereditary motor neuropathy (dHMN) with an autosomal recessive pattern. Methods Whole‐exome sequencing was conducted in two siblings and was combined with segregation analysis. Additionally, 83 unrelated dHMN patients with unknown genetic cause were screened. RNA analysis was performed using blood lymphocytes and HEK293 cells transfected with mutant plasmids. Immunohistochemistry and Western blot analysis was applied to the nerve tissue. The enzymatic activities of mutant proteins were measured in the cultured cells to verify the pathogenicity of variants. Results The clinical features of the patients showed late‐onset phenotype of distal motor neuropathy without sensory involvement. We identified that compound heterozygous variants of c.1342C>T and c.2071_2072delGCinsTT in the membrane metalloendopeptidase (MME) gene co‐segregated with the phenotype in a dHMN family. In an additional group of 83 patients with dHMN, compound heterozygous variants of c.1416+2T>C and c.2027C>T in MME were identified in one patient. The splice site variant c.1416+2T>C results in skipping of exon 13. The stop variant c.1342C>T induces mRNA degradation via nonsense‐mediated mRNA decay. Transcript levels of MME in the lymphocytes showed no significant differences between the patients and controls. We also identified that MME variants were associated with mild decrease in protein expression in the sural nerve and significant impairments of enzymatic activity. Interpretation Variants in the MME gene were associated with not only a Charcot‐Marie‐Tooth neuropathy phenotype but also with an autosomal‐recessive dHMN phenotype. Loss of function may play a role in the pathogenesis of dHMN.
- Subjects :
- 0301 basic medicine
Male
Adolescent
Mutant
Neurosciences. Biological psychiatry. Neuropsychiatry
Sural nerve
Genes, Recessive
medicine.disease_cause
Compound heterozygosity
03 medical and health sciences
Exon
Young Adult
0302 clinical medicine
medicine
Humans
RC346-429
Gene
Loss function
Research Articles
Mutation
business.industry
General Neuroscience
Middle Aged
Phenotype
Molecular biology
Pedigree
030104 developmental biology
HEK293 Cells
Female
Neprilysin
Neurology. Diseases of the nervous system
Neurology (clinical)
business
Hereditary Sensory and Motor Neuropathy
030217 neurology & neurosurgery
RC321-571
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 23289503
- Volume :
- 6
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Annals of Clinical and Translational Neurology
- Accession number :
- edsair.doi.dedup.....a102aa07dc610a6af11f83f8374ff06d