Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral.

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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) Hee-Jin Kim, Kwang-Min Sohn, Michael E. Shy, Karen M. Krajewski, Miok Hwang, June-Hee Park, Sue-Yon Jang, Hong-Hee Won, Byung-Ok Choi, Sung Hwa Hong, Byoung-Joon Kim, Yeon-Lim Suh, Chang-Seok Ki, Soo-Youn Lee, Sun-Hee Kim, Jong-Won Kim The American Journal of Human Genetics Volume 81, Issue 3, Pages 552-558 (September 2007) DOI: 10.1086/519529 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of the Korean family with CMTX5 (A) and the family of European descent with RCS (B). Affected male patients are indicated by blackened boxes and the obligate carrier females by circles with central dots. The individuals whose blood was drawn for the present study are marked with asterisks (*). The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 Sural nerve biopsy findings of a patient with CMTX5. A, Histological examination of the sural nerve biopsy sample revealed loss of myelinated nerve fibers and interstitial fibrosis (Luxol-fast blue, ×400). B, Electron micrograph of the sural nerve showed myelinated axons surrounded by concentrically arranged cytoplasmic processes of Schwann cells forming an “onion bulb.” The arrow indicates a remyelinating axon with an abnormally thin myelin sheath. The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 The transcript map of the region on chromosome band Xq22.3 within the CMTX5 locus and the genomic structure of PRPS1 with seven coding exons. Black bars represent coding sequences, and gray bars represent UTRs. All seven coding exons of PRPS1 were amplified and directly sequenced, according to standard procedures. The patients with CMTX5 had a missense mutation in exon 3 (blue circle), and the patients with RCS had a missense mutation in exon 2 (red circle). Tel = telomeric; Cen = centromeric. The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 A, The chromatograms of the PRPS1 mutations detected by direct sequencing. M115T in patients with CMTX5 (left panel) and E43D in patients with RCS (right panel). B, The affected amino acids are perfectly conserved across different species. The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5 Multiple sequence alignment of PRPS1 by ClustalW, showing the degree of conservation of the amino acid sequences of the PRPS1 protein across different species. Homo = Homo sapiens; Canis = Canis familiaris; Rattus = Rattus norvegicus; Mus = Mus musculus; Danio = Danio rerio; Silurana = Silurana tropicalis. The reference amino acid sequences for alignment are same as in figure 4B. The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 6 PRPS enzyme activity, determined by measuring the degree of generation of AMP, the end product of PRPS enzyme, in cultured fibroblasts. The activity was decreased in patients with CMTX5 (CMTX5:IV-1, IV-11, and III-18) compared with unaffected family members and unrelated control individuals (CMTX5:III-13, VI-2 and C-1, C-2). The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 7 A, The locations of the mutations on the ribbon diagram of the PRPS1 monomer.11 M115T in CMTX5 on the α-helix of N-terminal domain (blue) and E43D in RCS on the “flag” region of the N-terminal domain (green). B, Hexameric structure and subunits of PRPS1. Reprinted with permission from Nature Publishing Group.11 The American Journal of Human Genetics 2007 81, 552-558DOI: (10.1086/519529) Copyright © 2007 The American Society of Human Genetics Terms and Conditions