title: 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.
authors: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea.
authors: Hee-Jin
authors: HJ
authors: Kim
authors: Kwang-Min
authors: KM
authors: Sohn
authors: Michael E
authors: ME
authors: Shy
authors: Karen M
authors: KM
authors: Krajewski
authors: Miok
authors: M
authors: Hwang
authors: June-Hee
authors: JH
authors: Park
authors: Sue-Yon
authors: SY
authors: Jang
authors: Hong-Hee
authors: HH
authors: Won
authors: Byung-Ok
authors: BO
authors: Choi
authors: Sung Hwa
authors: SH
authors: Hong
authors: Byoung-Joon
authors: BJ
authors: Kim
authors: Yeon-Lim
authors: YL
authors: Suh
authors: Chang-Seok
authors: CS
authors: Ki
authors: Soo-Youn
authors: SY
authors: Lee
authors: Sun-Hee
authors: SH
authors: Kim
authors: Jong-Won
authors: JW
authors: Kim
mesh_terms: 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
chemical_list: D009711:Nucleotides; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase
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