Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies |
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Authors: | Sylvia Bort E Nelis Vincent Timmerman Teresa Sevilla Antonio Cruz-Martínez Francisco Martínez José M Millán Javier Arpa Juan J Vílchez Felix Prieto Christine Van Broeckhoven F Palau |
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Institution: | (1) Genetics Unit, Hospital Universitari La Fe, Av. Campanar 21, E-46009 Valencia, Spain Tel.: +34-6-386-27-00 ext. 5163; Fax: +34-6-386-87-89 ; e-mail: palau@evalgb.geneti.uv.es, ES;(2) Neurogenetics Laboratory, Flanders Interuniversity Institute for Biotechnology, Born Bunge Foundation (B.B.S.), University of Antwerp (U.I.A.), Department of Biochemistry, B-2610 Antwerp, Belgium, BE;(3) Department of Neurology, Hospital Universitari La Fe, E-46009 Valencia, Spain, ES;(4) Electromyography Unit, Hospital La Luz, Madrid, Spain, ES;(5) Department of Neurology, Hospital La Paz, Madrid, Spain, ES |
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Abstract: | Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP) are two inherited peripheral
neuropathies. The most prevalent mutations are a reciprocal 1.5-Mb duplication and 1.5-Mb deletion, respectively, at the CMT1A/HNPP
locus on chromosome 17p11.2. Point mutations in the coding region of the myelin genes, peripheral myelin protein 22 (PMP22),
myelin protein zero (MPZ) or connexin 32 (Cx32) have been reported in CMT patients, including CMT type 1 (CMT1), CMT type
2 (CMT2) and Déjérine-Sottas neuropathy (DS) patients, and only in the coding region of PMP22 in HNPP families lacking a deletion.
We have investigated point and small mutations in the MPZ, PMP22 and Cx32 genes in a series of patients of Spanish ancestry:
47 CMT patients without duplications, and 5 HNPP patients without deletions. We found 15 different mutations in 16 CMT patients
(34%). Nine different mutations in ten patients were detected in the Cx32 gene, this being the most frequently involved gene
in this series, whereas five mutations involved the MPZ gene and only one the PMP22 gene. Six out of nine nucleotide substitutions
in the Cx32 gene involved two codons encoding arginine at positions 164 and 183, suggesting that these two codons may constitute
two Cx32 regions prone to mutate in the Spanish population. Analysis of HNPP patients revealed a 5′ splicing mutation in intron
1 of the PMP22 gene in a family with autosomal dominance, which confirms allelic heterogeneity in HNPP. Ectopic mRNA analysis
on leukocytes suggests that this mutation might behave as a null allele.
Received: 25 July 1996 / Revised: 15 November 1996 |
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