Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.
Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder that has been associated with alterations of several proteins: peripheral myelin protein 22, myelin protein zero, connexin 32, early growth response factor 2, periaxin, myotubularin related protein 2, N-myc downstream regulated gene 1 product, neurofilament light chain, and kinesin 1B. To determine the frequency of mutations in these genes among patients with CMT or a related peripheral neuropathy, we identified 153 unrelated patients who enrolled prior to the availability of clinical testing, 79 had a 17p12 duplication (CMT1A duplication), 11 a connexin 32 mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein 22 mutation, 1 an early growth response factor 2 mutation, 1 a periaxin mutation, 0 a myotubularin related protein 2 mutation, 1 a neurofilament light chain mutation, and 50 had no identifiable mutation; the N-myc downstream regulated gene 1 and the kinesin 1B gene were not screened for mutations. In the process of screening the above cohort of patients as well as other patients for CMT-causative mutations, we identified several previously unreported mutant alleles: two for connexin 32, three for myelin protein zero, and two for peripheral myelin protein 22. The peripheral myelin protein 22 mutation W28R was associated with CMT1 and profound deafness. One patient with a CMT2 clinical phenotype had three myelin protein zero mutations (I89N+V92M+I162M). Because one-third of the mutations we report arose de novo and thereby caused chronic sporadic neuropathy, we conclude that molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy.
Boerkoel
Cornelius F
CF
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Takashima
Hiroshi
H
Garcia
Carlos A
CA
Olney
Richard K
RK
Johnson
John
J
Berry
Katherine
K
Russo
Paul
P
Kennedy
Shelley
S
Teebi
Ahmad S
AS
Scavina
Mena
M
Williams
Lowell L
LL
Mancias
Pedro
P
Butler
Ian J
IJ
Krajewski
Karen
K
Shy
Michael
M
Lupski
James R
JR
D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D003638:Deafness / Q000235:genetics; D051767:Early Growth Response Protein 2; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018993:Myelin P0 Protein / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D014157:Transcription Factors; D000097002:Gap Junction beta-1 Protein; C497326:EGR2 protein, human; C073687:PMP22 protein, human