PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

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PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy Christel Thauvin-Robinet, Martine Auclair, Laurence Duplomb, Martine Caron-Debarle, Magali Avila, Judith St-Onge, Martine Le Merrer, Bernard Le Luyer, Delphine Héron, Michèle Mathieu-Dramard, Pierre Bitoun, Jean-Michel Petit, Sylvie Odent, Jeanne Amiel, Damien Picot, Virginie Carmignac, Julien Thevenon, Patrick Callier, Martine Laville, Yves Reznik, Cédric Fagour, Marie-Laure Nunes, Jacqueline Capeau, Olivier Lascols, Frédéric Huet, Laurence Faivre, Corinne Vigouroux, Jean-Baptiste Rivière The American Journal of Human Genetics Volume 93, Issue 1, Pages 141-149 (July 2013) DOI: 10.1016/j.ajhg.2013.05.019 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Appearance of Individuals with SHORT Syndrome, Test Results for Oral Glucose Tolerance, and Distribution of PIK3R1 Mutations (A–H) Photos of subjects P1 (A–C), P2 (D), and P3 (E) and familial pedigree and photos of subject P5 (F–H). Subjects presented with a typical triangular facial shape, deep-set eyes, thin and hypoplastic alae nasi, a small chin, mild midfacial hypoplasia, and lipoatrophy. We obtained written consent to publish photographs of the subjects. (I) Test results for oral glucose tolerance show hyperglycemia in subjects P3 (at 13.5 years of age) and P7 and increased serum insulin levels in all affected children (subjects P1, P2, and P3). (J) Schematic representation of the three isoforms encoded by PIK3R1, their functional domains, and the alterations identified in individuals with SHORT syndrome. The American Journal of Human Genetics 2013 93, 141-149DOI: (10.1016/j.ajhg.2013.05.019) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Cellular Insulin Resistance in Subjects with PIK3R1 Mutations (A and B) PIK3R1 levels and short-term effects of insulin on proximal PI3K-dependent insulin signaling in fibroblasts from affected individuals (P1 and P2) and controls. PIK3R1 levels (A) and the effect of insulin on AKT activation (B) were evaluated by immunoblotting on whole-cell lysates. Intensities were quantified by densitometry scanning. PIK3R1 levels and AKT phosphorylation levels were normalized to β-actin and total AKT, respectively. Representative immunoblots are shown. The following abbreviation is used: p-AKT-ser473, phospho-AKT-ser473. (C) Short-term effects of insulin on distal PI3K-dependent signaling. The effects of insulin on glycogen synthesis and glucose transport were evaluated by the incorporation of 14C-glucose into glycogen and the cellular uptake of 3H-2-deoxy-D-glucose, respectively. In fibroblasts from control subjects and individuals P1 and P2, basal glycogen synthesis was 22.3 ± 1.6, 54.6 ± 6.0, and 52.5 ± 0.4 pmoles of glucose incorporated into glycogen per mg protein per hour, respectively, and basal glucose transport was 10.5 ± 1.1, 23.2 ± 2.4, and 11.4 ± 1.5 pmole of cellular 2-deoxyglucose per mg protein per min, respectively. Results are expressed as means ± SEM. Asterisks indicate a statistically significant difference compared to control cells (p < 0.05, Student’s t test). The American Journal of Human Genetics 2013 93, 141-149DOI: (10.1016/j.ajhg.2013.05.019) Copyright © 2013 The American Society of Human Genetics Terms and Conditions