Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene.
BACKGROUND
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A.


METHODS
We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products.


RESULTS
A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication.


CONCLUSIONS
The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.
Roa
B B
BB
Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX 77030-3498.
Garcia
C A
CA
Suter
U
U
Kulpa
D A
DA
Wise
C A
CA
Mueller
J
J
Welcher
A A
AA
Snipes
G J
GJ
Shooter
E M
EM
Patel
P I
PI
Lupski
J R
JR
D000595:Amino Acid Sequence; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D002886:Chromosomes, Human, Pair 17; D016373:DNA, Antisense; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D009692:Nucleic Acid Heteroduplexes; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D016373:DNA, Antisense; D009692:Nucleic Acid Heteroduplexes