CMTX5: Mutations in PRPS1 Which Encodes the Phosphoribosyl Pyrophosphate

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Am J Hum Genet. 2007 Sep;81(3):552-8.

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).

Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY,

Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim

JW.

Department of Laboratory Medicine and Genetics, Samsung Medical

Center, Sungkyunkwan University School of Medicine, Gangnam-gu,

Seoul, Korea.

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.