Abstract
We have identified a large US family with 33 affected individuals with Charcot-Marie-Tooth (CMT) syndrome, sensorineural deafness and evidence of anticipation. Originally reportedby Kouseff et at (1982), this disorder has not been previously characterized at the molecular level. All affected individuals in this family demonstrate slow nerve conduction velocities resembling CMT1A, and electron microscopy of sural nerve reveals severe demyelination of axons. There is moderate to profound deafness by adulthood. Audiological studies suggest auditory neural dysfunction as well as a minor degree of peripheral cochlear impairment. Members of the younger generations exhibit earlier onset and progressively more severe manifestation of the disease (p<0.05); the proband and another male dying in infancy from complications of CMT. Individuals from this family do not have the common 1.5 Mb duplication of CMT type 1A. We have mapped the disease to a0.6 Mb interval on chromosome 17p11.2 - p12 (Z max 9.01 with D17S1357 at theta=0.03). This critical region lies within the CMT type 1A duplication region but excludes the DFNB3 recessive deafness locus. Sequence analysis of PMP22 detected a unique G to C transversion at position 248 in exon 4 predicted to result in a substitution ofproline for a conservedalanine at codon 67 in transmembrane domain 2. This mutation was only observed in affected individuals, and not in 50 unrelated controls. The observed anticipation could not be explained by expansions of the three known trinucleotide repeats. PMP22 glycoprotein probably functions as a gap protein and is highly expressed by Schwann cells in compact myelin of the peripheral nervous system. PMP22 is structurally similar to theconnexins and point mutations in the transmembrane region of the latter have been implicated insyndromic and non-syndromic deafness. Presently the only known gene expressed in the cochlear, that maps to position 17p11.2-pl214, this study illustrates the pleiotrophic nature of PMP22 and its role in hearing.
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Kimonis, V., Kovach, M., Lin, JP. et al. A unique point mutation in the PMP22 gene is associated with Deafness, Charcot-Marie-Tooth and Anticipation. Genet Med 1, 44 (1999). https://doi.org/10.1097/00125817-199901000-00018
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DOI: https://doi.org/10.1097/00125817-199901000-00018