Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta Figen Seymen, Youn Jung Kim, Ye Ji Lee,

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Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta Figen Seymen, Youn Jung Kim, Ye Ji Lee, Jenny Kang, Tak-Heun Kim, Hwajung Choi, Mine Koruyucu, Yelda Kasimoglu, Elif Bahar Tuna, Koray Gencay, Teo Jeon Shin, Hong-Keun Hyun, Young-Jae Kim, Sang-Hoon Lee, Zang Hee Lee, Hong Zhang, Jan C-C. Hu, James P. Simmer, Eui-Sic Cho, Jung-Wook Kim The American Journal of Human Genetics Volume 99, Issue 5, Pages 1199-1205 (November 2016) DOI: 10.1016/j.ajhg.2016.09.018 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigrees, Frontal Clinical Photos, and Panoramic Radiographs Clinical images and panoramic radiographs showed generalized hypoplastic AI in deciduous and permanent dentitions. Some teeth had external staining. Plus (+) symbols indicate individuals who participated in this study, and a black arrow identifies the proband in each family. Numbers in the symbol indicate the number of siblings. The American Journal of Human Genetics 2016 99, 1199-1205DOI: (10.1016/j.ajhg.2016.09.018) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Spatial Localization of ACPT and Amelogenin Immunoreactivity of both amelogenin (AMEL) and ACPT were detected in secretory ameloblasts (black arrows) of postnatal-day-8 mouse molars. Upper panels: 100×, scale bar represents 100 μm; lower panels: 400×, scale bar represents 20 μm. The American Journal of Human Genetics 2016 99, 1199-1205DOI: (10.1016/j.ajhg.2016.09.018) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 ACPT Diagram, Protein Structure, and Amino Acid Sequence Alignment (A) Coding exons are shown as gray boxes, and the UTR is shown as a white box. Mutations identified in this report are shown above exons. (B) Domain structure of ACPT. (C) Amino acid sequence alignment of various species. Amino acids affected by the mutations are indicated with bold characters and gray highlight. The American Journal of Human Genetics 2016 99, 1199-1205DOI: (10.1016/j.ajhg.2016.09.018) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 4 In Silico Analysis of the Mutations (A) Three-dimensional structure of a homodimer generated with the PyMOL program. Mutated amino acids are indicated in the diagram. Both Ala128 and Glu133 are located in a loop involved in homodimerization. Arg76 is located in an α-helix that interacts with a loop in the homodimer partner. Arg111 is located in an α-helix near the catalytic core and has direct interactions with catalytic motifs (His41 and His288), and Ser238 is located in an α-helix near the active catalytic core. (B) The p.Arg111Cys substitution results in total loss of interactions with two important amino acids (His41 and His288) residing in the catalytic core of ACPT. (C) The p.Ser238Leu substitution loses the interaction with Leu234 in the same α-helix. The size of the side chain is increased significantly (red arrows). (D) The p.Arg76Cys substitution results in total loss of the interactions with Pro132 within a loop of the homodimer partner; in addition, both the charge and size of the side chain are altered significantly (from polar with a −4.5 hydropathy index to nonpolar with a 2.5 hydropathy index). (E) The p.Ala128Pro substitution creates new interactions with Ala127 and Ser131. The size of the side chain is increased significantly. (F) The p.Glu133Lys substitution results in a loss of interaction with Arg137 and a change of the charge from negative to positive. The American Journal of Human Genetics 2016 99, 1199-1205DOI: (10.1016/j.ajhg.2016.09.018) Copyright © 2016 American Society of Human Genetics Terms and Conditions