Mutations in PURA Cause Profound Neonatal Hypotonia, Seizures, and Encephalopathy in 5q31.3 Microdeletion Syndrome Seema R. Lalani, Jing Zhang, Christian P.

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Mutations in PURA Cause Profound Neonatal Hypotonia, Seizures, and Encephalopathy in 5q31.3 Microdeletion Syndrome Seema R. Lalani, Jing Zhang, Christian P. Schaaf, Chester W. Brown, Pilar Magoulas, Anne Chun-Hui Tsai, Areeg El-Gharbawy, Klaas J. Wierenga, Dennis Bartholomew, Chin-To Fong, Tina Barbaro-Dieber, Mary K. Kukolich, Lindsay C. Burrage, Elise Austin, Kory Keller, Matthew Pastore, Fabio Fernandez, Timothy Lotze, Angus Wilfong, Gabriela Purcarin, Wenmiao Zhu, William J. Craigen, Marianne McGuire, Mahim Jain, Erin Cooney, Mahshid Azamian, Matthew N. Bainbridge, Donna M. Muzny, Eric Boerwinkle, Richard E. Person, Zhiyv Niu, Christine M. Eng, James R. Lupski, Richard A. Gibbs, Arthur L. Beaudet, Yaping Yang, Meng C. Wang, Fan Xia The American Journal of Human Genetics Volume 95, Issue 5, Pages 579-583 (November 2014) DOI: 10.1016/j.ajhg.2014.09.014 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 PURA Mutations in the Affected Human Subjects and Functions of the PURA Ortholog in Model System C. elegans (A) PURA is located in chromosomal region 5q31.2 (according to the UCSC Genome Browser). A single exon (blue) encodes a protein with three PUR motifs, as shown in green. On the protein diagram, missense and in-frame-deletion mutations are brown, and the truncating mutations are shown in red. (B) Six subjects with de novo PURA mutations are shown. The craniofacial features are mainly characterized by myopathic facies. For whom clinical photographs are shown, informed consent specifically agreeing to publish these photographs in medical publications was obtained. (C) DNA staining in the germline of a wild-type C. elegans animal. Yellow dashed lines indicate differentiated oocytes. (D) Oocytes were absent in the plp-1-mutant animal with smaller gonads. Wild-type (N2) and RB1711 (plp-1(ok2155)IV) animals were obtained from the Caenorhabditis Genetics Center. C. elegans were grown on standard nematode growth media plates (containing 5 mg/l cholesterol) with E. coli OP50 at 25°C according to standard protocols. DAPI staining was performed at room temperature. The germline was dissected out from young adult worms. (E) Average speed of individual worm movement (wild-type n = 14, plp-1 n = 12). The p value was obtained by a one-tailed Student’s t test. Error bars in the scattered dot plot represent the mean and the SEM. Spontaneous movement of age-synchronized worms on standard worm plates was recorded for 15 s with an SMZ1500 stereo microscope (Nikon) connected to a C11440 camera (Hamamatsu). Individual worms were tracked with NIS Elements AR 2D tracking imaging software (Nikon), and the average velocity (μm/s) was calculated. Representative recording of wild-type worms and plp-1 mutants are shown in Movies S1 and S2, respectively. The American Journal of Human Genetics 2014 95, 579-583DOI: (10.1016/j.ajhg.2014.09.014) Copyright © 2014 The American Society of Human Genetics Terms and Conditions