Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral Neuropathy with Hearing Loss and Optic Neuropathy (CMTX5)

Abstract

We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

X‐linked neuropathy of the Charcot–Marie–Tooth type

“…The phenotype includes peripheral neuropathy, earlyonset sensorineural deafness, and visual impairment due to optic neuropathy [40]. histopathology A sural nerve biopsy revealed severe loss of myelinated fibers associated with endoneurial fibrosis.…”

“…On electron microscopy, concentrically arranged Schwann cell processes were seen forming onion bulb like structures adjacent to abnormally thin myelin sheaths around remyelinating axons [40].…”

Audiological Findings in Charcot–Marie–Tooth Disease Type 4C

“…Hearing loss due to auditory nerve dysfunction was first described in 1979 and was subsequently described in patients with diverse subtypes of CMT [2,3] . It can occur as a constant phenotypic feature like in CMT4D or CMTX5 or as an occasional associated feature as in MPZ, PMP22, GJB1, NEFL, and SH3TC2 mutations [4][5][6][7][8][9][10] .…”

In Silico Functional Assessment of Sequence Variations: Predicting Phenotypic Functions of Novel Variations

“…Although most CVs are functionally neutral, some CVs affect phenotype, including nonsynonymous single nucleotide polymorphisms (nsSNPs) that contribute to normal phenotypic differences in hair color, skin color (Sulem et al, 2007;Han et al, 2008), and disease susceptibility (WTCCC, 2007;Amos et al, 2008;Harley et al, 2008;Tenesa et al, 2008). Other CVs result in deleterious missense mutations that cause highly penetrant Mendelian-inherited diseases (Kim et al, 2007). These deleterious mutations have been of great interest in biomedical research and clinical practice for decades and account for approximately half of the genetic variations that are known to cause disease.…”