Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X- linked Sensorineural Deafness, DFN2 Xuezhong Liu, Dongyi Han, Jianzhong Li,

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Loss-of-Function Mutations in the PRPS1 Gene Cause a Type of Nonsyndromic X- linked Sensorineural Deafness, DFN2 Xuezhong Liu, Dongyi Han, Jianzhong Li, Bing Han, Xiaomei Ouyang, Jing Cheng, Xu Li, Zhanguo Jin, Youqin Wang, Maria Bitner- Glindzicz, Xiangyin Kong, Heng Xu, Albena Kantardzhieva, Roland D. Eavey, Christine E. Seidman, Jonathan G. Seidman, Li L. Du, Zheng-Yi Chen, Pu Dai, Maikun Teng, Denise Yan, Huijun Yuan The American Journal of Human Genetics Volume 86, Issue 1, Pages 65-71 (January 2010) DOI: 10.1016/j.ajhg.2009.11.015 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Chinese Family GZ-Z052 with X-linked Heriditary NSHL (A) Audiograms of some affected male and female subjects (red, right ear; black, left ear). IV-21, who has a history of the use of aminoglycosides, had exactly same audiogram pattern as that of IV-9 and IV-36, suggesting that his hearing impairment was not due to aminoglycoside exposure. The hearing impairment of female carriers is progressive but not completely linked with increasing age. (B) Haplotype analysis of the Chinese family GZ-Z052. The segregating haplotype associated with the NSHL is indicated by a black bar, delimited by markers DXS8020 and DXS8055 on chromosome Xq22. The American Journal of Human Genetics 2010 86, 65-71DOI: (10.1016/j.ajhg.2009.11.015) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Mapping Intervals and Mutation Analysis of the Four DFN2 Families (A) Idiogram of the X chromosome with the described DFN2 loci. The linkage intervals and flanking markers of four DFN2 families are indicated in colored fonts and bars (red, Chinese family GZ-Z052; green, British American family; black, Chinese family reported by Cui et al.;6 blue: American family). (B) The genomic structure of PRPS1 depicting the positions of four DFN2 mutations. (C–F) DNA sequence chromatograms showing four different missense mutations identified in affected males of four DFN2 families, compared to wild-type controls. The American Journal of Human Genetics 2010 86, 65-71DOI: (10.1016/j.ajhg.2009.11.015) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Structure of PRS-I in Complex with AMP The substrate-binding pocket of PRS-I consists of a metal ion-binding site (gray sphere), an ATP-binding site (represented by AMP moiety of ATP as sticks), and an R5P-binding site (a SO42− ion occupies the position of the 5′ phosphate of R5P). In this figure, two different asymmetric subunits of PRS-I (aquamarine and pale yellow) form a part of the hexamer interface, and all of the structural elements in the pale yellow subunit are tagged with an apostrophe. (A) Location of Asp65′ (magenta sticks) and Lys34′ (green sticks between the β2′ strand and loop3′). (B) Location of Ala87 (green sticks in the purple β5 strand) and the ATP-binding loop (marine loop7). (C) Location of Ile290 (green sticks in the β14 strand) and of loop22 (deep blue). (D) Location of Gly306 (green sticks in the β14 strand) and the allosteric site of PRS-I (an SO42− ion occupies the position of the β-phosphate of ADP). The American Journal of Human Genetics 2010 86, 65-71DOI: (10.1016/j.ajhg.2009.11.015) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Prps1 Expression in the Mouse Inner Ear (A) With an antisense probe, Prps1 was observed at E18.5 as robustly expressed in the cochlear hair cells (HC), the Claudius cells (CC), and the greater epithelial ridge (GER), but not in other cochlear supporting cells. (B) A sense control probe did not produce any signals. (C) At postnatal day 6, HC and CC expression of Prps1 was maintained, whereas expression in the GER was reduced. Prps1 was also expressed in the spiral ganglions (SG) at this stage. (D) A sense control probe did not produce any signal. Magnification 20×. The American Journal of Human Genetics 2010 86, 65-71DOI: (10.1016/j.ajhg.2009.11.015) Copyright © 2010 The American Society of Human Genetics Terms and Conditions