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).
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.
Kim
Hee-Jin
HJ
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea.
Sohn
Kwang-Min
KM
Shy
Michael E
ME
Krajewski
Karen M
KM
Hwang
Miok
M
Park
June-Hee
JH
Jang
Sue-Yon
SY
Won
Hong-Hee
HH
Choi
Byung-Ok
BO
Hong
Sung Hwa
SH
Kim
Byoung-Joon
BJ
Suh
Yeon-Lim
YL
Ki
Chang-Seok
CS
Lee
Soo-Youn
SY
Kim
Sun-Hee
SH
Kim
Jong-Won
JW
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009711:Nucleotides / Q000096:biosynthesis / Q000235:genetics; D009901:Optic Nerve Diseases / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D012268:Ribose-Phosphate Pyrophosphokinase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D044465:White People / Q000235:genetics
D009711:Nucleotides; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase
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