Exome Sequencing Reveals a Novel PRPS1 Mutation in a Family with CMTX5 without Optic Atrophy

Abstract

Background: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is caused by mutations in the gene encoding phosphoribosyl pyrophosphate synthetase I (PRPS1). There has been only one case report of CMTX5 patients. The aim of this study was to identify the causative gene in a family with CMTX with peripheral neuropathy and deafness.

Case report: A Korean family with X-linked recessive CMT was enrolled. The age at the onset of hearing loss of the male proband was 5 months, and that of steppage gait was 6 years; he underwent cochlear surgery at the age of 12 years. In contrast to what was reported for the first patients with CMTX5, this patient did not exhibit optic atrophy. Furthermore, there was no cognitive impairment, respiratory dysfunction, or visual disturbance. Assessment of his family history revealed two male relatives with very similar clinical manifestations. Electrophysiological evaluations disclosed sensorineural hearing loss and peripheral neuropathy. Whole-exome sequencing identified a novel p.Ala121Gly (c.362C>G) PRPS1 mutation as the underlying genetic cause of the clinical phenotype.

Conclusions: A novel mutation of PRPS1 was identified in a CMTX5 family in which the proband had a phenotype of peripheral neuropathy with early-onset hearing loss, but no optic atrophy. The findings of this study will expand the clinical spectrum of X-linked recessive CMT and will be useful for the molecular diagnosis of clinically heterogeneous peripheral neuropathies.

Keywords: Charcot-Marie-Tooth disease type X5; deafness; exome; mutation; phosphoribosyl pyrophosphate synthetase I gene.

Fig. 1

Pedigree, sequencing, and conservation analysis. A: Pedigree of a Korean family with X-linked Charcot-Marie-Tooth disease type 5. Open symbols, unaffected individuals; filled symbols, affected individuals; circles with a dot inside, putative carriers of PRPS1 mutation; arrow, proband; asterisks, individuals whose DNA was used for DNA sequencing. B: Sequencing chromatograms showing the PRPS1c.362C>G (Ala-121Gly) mutation. The affected proband (IV-1) is hemizygous, whereas his unaffected mother is heterozygous for this locus. Vertical arrows indicate the mutation site. C: Conservation of amino acid sequences among different species. The analysis was performed using MEGA5 (ver. 5.05) software. The mutation site and its neighboring sequences were highly conserved among the different species.