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PMP22 Mutations In DÉJÈRine‐Sottas Disease: A Mutational “Hot Spot” On Codon 72
Author(s) -
Milani M,
Milani N,
Pareyson D,
Gorni K,
Merlini L,
Mostacciuolo ML,
Taroni F.
Publication year - 2001
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1046/j.1529-8027.2001.01007-36.x
Subject(s) - missense mutation , exon , gene duplication , peripheral myelin protein 22 , genetics , mutation , gene , biology , myelin , stop codon , compound heterozygosity , medicine , endocrinology , central nervous system
Increased dosage of the gene encoding the peripheral myelin protein PMP22 is the most common molecular mechanism underlying the demyelinating form of Charcot‐Marie‐Tooth disease (CMT1A). It results from the duplication of a 1.5‐Mb tract on chr. 17p11.2 which encompasses the PMP22 gene. Mutations in this gene can also cause CMT1A and are often associated with more severe phenotypes such as Déjèrine‐Sottas disease (DSD) and congenital hypomyelinating neuropathy (CHN). We have analyzed the PMP22 gene in 20 unrelated patients affected with a severe form of demyelinating motor and sensory neuropathy (severe CMT1 or DSD). All the patients had been found negative for the common CMT1A duplication and for mutations in the myelin protein P 0 gene ( MPZ ). Direct sequence analysis of PMP22 uncovered the presence of missense mutations in 3 patients diagnosed as having DSD. In each case, the mutation was heterozygous and was not carried by any of the nonaffected parents, thus indicating that it was a de novo dominant mutation. Patient #1, a 3‐y‐old boy, carried a C‐to‐T transition in PMP22 exon 4 which would result in the amino acid substitution of Leu‐80 with Pro in the 2nd transmembrane domain of the protein. This mutation had been previously observed in another DSD patient (Tyson, 1997). Patient #2, a 3‐y‐old girl, and patient #3 carried the same mutation, the 215C‐to‐T transition in exon 4. Interestingly, patient #3 was a 35‐y‐old man born of consanguineous healthy parents. The disease had started during the first years of life and the patient had become wheelchair‐bound at the age of 28 y. The 215C‐to‐T mutation eliminates a Taq I restriction site and results in the substitution of Ser‐72 (TCG) with Leu (TTG) in the 2nd transmembrane domain of PMP22. Approx. 40 different PMP22 mutations are currently listed in the European CMT Consortium Database. In the majority of cases, the mutations have been identified in single or very few patients, with the only exception of the Ser72Leu substitution. Including the two unrelated patients reported here, this mutation has been thus far described in a total of 7 patients. The mutation, which occurs within a CpG dinucleotide, exhibits phenotypic heterogeneity and has been observed in both DSD (6) and CHN (1) cases. In conclusion, PMP22 mutations are rare causes of genetic neuropathies. Given the limited number of such mutations, the recurrence of substitutions at codon 72 would indicate that this may represent a mutational “hot spot”. We therefore suggest that sequence analysis of PMP22 exon 4 should routinely precede analysis of the remaining exons and intron/exon boundaries.