MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.
Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.
Verhoeven
Kristien
K
Peripheral Neuropathy Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium.
Claeys
Kristl G
KG
Züchner
Stephan
S
Schröder
J Michael
JM
Weis
Joachim
J
Ceuterick
Chantal
C
Jordanova
Albena
A
Nelis
Eva
E
De Vriendt
Els
E
Van Hul
Matthias
M
Seeman
Pavel
P
Mazanec
Radim
R
Saifi
Gulam Mustafa
GM
Szigeti
Kinga
K
Mancias
Pedro
P
Butler
Ian J
IJ
Kochanski
Andrzej
A
Ryniewicz
Barbara
B
De Bleecker
Jan
J
Van den Bergh
Peter
P
Verellen
Christine
C
Van Coster
Rudy
R
Goemans
Nathalie
N
Auer-Grumbach
Michaela
M
Robberecht
Wim
W
Milic Rasic
Vedrana
V
Nevo
Yoram
Y
Tournev
Ivajlo
I
Guergueltcheva
Velina
V
Roelens
Filip
F
Vieregge
Peter
P
Vinci
Paolo
P
Moreno
Maria Teresa
MT
Christen
H-J
HJ
Shy
Michael E
ME
Lupski
James R
JR
Vance
Jeffery M
JM
De Jonghe
Peter
P
Timmerman
Vincent
V
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004594:Electrophysiology; D020558:GTP Phosphohydrolases; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008854:Microscopy, Electron; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index; D013497:Sural Nerve / Q000648:ultrastructure
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human