MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability.
Brain
; 140(8): 2093-2103, 2017 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-28633435
ABSTRACT
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Acetiltransferasas
/
Enfermedad de Charcot-Marie-Tooth
/
Predisposición Genética a la Enfermedad
/
Péptidos y Proteínas de Señalización Intracelular
/
Discapacidad Intelectual
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Adolescent
/
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Brain
Año:
2017
Tipo del documento:
Article
País de afiliación:
Finlandia