title: A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.
abstract: Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: B-O
authors.initials: BO
authors.lastname: Choi
authors.forename: K
authors.initials: K
authors.lastname: Nakhro
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.forename: Y S
authors.initials: YS
authors.lastname: Hyun
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Kanwal
authors.forename: S-C
authors.initials: SC
authors.lastname: Jung
authors.forename: K W
authors.initials: KW
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005190:Family; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007723:Korea; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: Charcot-Marie-Tooth disease 2A; Korean; exome; genotype-phenotype correlation; mitofusin 2