REPORT PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy Christel Thauvin-Robinet, 1,2,25, * Martine Auclair, 3,4,5,25 Laurence Duplomb, 1,25 Martine Caron-Debarle, 3,4,5 Magali Avila, 1 Judith St-Onge, 1,6 Martine Le Merrer, 7 Bernard Le Luyer, 8 Delphine He ´ron, 9 Miche `le Mathieu-Dramard, 10 Pierre Bitoun, 11 Jean-Michel Petit, 12 Sylvie Odent, 13,14 Jeanne Amiel, 4 Damien Picot, 1 Virginie Carmignac, 1 Julien Thevenon, 1,2 Patrick Callier, 1,15 Martine Laville, 16,17 Yves Reznik, 18,19,20 Ce ´dric Fagour, 21 Marie-Laure Nunes, 21 Jacqueline Capeau, 3,4,5,22 Olivier Lascols, 3,4,5,23 Fre ´de ´ric Huet, 1,24 Laurence Faivre, 1,2 Corinne Vigouroux, 3,4,5,22 and Jean-Baptiste Rivie `re 1,6, * Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syn- drome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutane- ous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retarda- tion. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a muta- tional hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85a, p55a, and p50a regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts. Insulin resistance is closely associated with many com- mon, complex, and multifactorial conditions, including obesity, type 2 diabetes, atherosclerosis, nonalcoholic fatty-liver disease, and polycystic-ovary syndrome. Rare monogenic forms of insulin resistance also exist, and iden- tifying the genetic basis of such phenotypes provides unique opportunities for deciphering the multiple molec- ular mechanisms leading to insulin resistance. 1 SHORT syndrome (MIM 269880)—whose acronym stands for short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay—is a developmental disorder of unknown genetic cause and is associated with generalized thin habitus despite normal food intake. Onset of insulin resistance and/or diabetes mellitus typically occurs in adolescence. 2 Although affected individuals frequently present with short stature and relative microcephaly when compared to unaffected family members, height is in the low-normal range in one-third of cases. Other features include charac- teristic facial dysmorphism, delayed bone age and gracile long bones, variable ocular anomalies, normal intellect or mild impairment with speech delay, frequent illnesses, and lack of subcutaneous fat with wrinkled skin and readily visible veins enhancing the progeroid appearance. 1 Equipe d’Accueil 4271, Ge ´ne ´tique des Anomalies du Developpement, Universite ´ de Bourgogne, F-21079 Dijon, France; 2 Centre de Ge ´ne ´tique et Centre de Re ´fe ´rence Anomalies du De ´veloppement et Syndromes Malformatifs de l’Interre ´gion Est, Centre Hospitalier Universitaire Dijon, F-21079 Dijon, France; 3 Institut National de la Sante ´ et de la Recherche Me ´dicale Unite ´ Mixte de Recherche S938, F-75012 Paris, France; 4 Centre de Recherche Saint-Antoine Unite ´ Mixte de Recherche S938, Universite ´ Pierre et Marie Curie – Paris 6, F-75005 Paris, France; 5 Institute of Cardiometabolism and Nutrition, Groupe Hospitalier Universitaire La Pitie ´ Salpe ˆtrie `re, F-75013 Paris, France; 6 Laboratoire de Ge ´ne ´tique Mole ´culaire, Centre Hospitalier Universitaire Dijon, F-21079 Dijon, France; 7 De ´partement de Ge ´ne ´tique, Ho ˆpital Necker Enfants Malades, F-75743 Paris, France; 8 Service de Pe ´diatrie, Centre Hospitalier Le Havre, F-76083 Le Havre, France; 9 De ´partement de Ge ´ne ´tique et Centre de Re ´fe ´rence ‘‘De ´ficiences Intellectuelles de Causes Rares,’’ La Pitie ´ Salpe ˆtrie `re, F-75651 Paris, France; 10 Service de Ge ´ne ´tique Clinique, Centre Hospitalier Universitaire Amiens, F-80054 Amiens, France; 11 Service de Pe ´diatrie, Centre Hospitalier Universitaire Jean Verdier, F-93143 Bondy, France; 12 Service d’Endocrinologie, Centre Hospitalier Universitaire Dijon, F-21079 Dijon, France; 13 Service de Ge ´ne ´tique Clinique, Centre Hospitalier Universitaire Rennes, F-35203 Rennes, France; 14 Centre National de la Recherche Scientifique Unite ´ Mixte de Recherche 6290, Institut Ge ´ne ´tique et De ´veloppement de Rennes, Universit _ e de Rennes 1, F-35203 Rennes, France; 15 Laboratoire de Cytoge ´ne ´tique, Centre Hospitalier Universitaire Dijon, F-21079 Dijon, France; 16 De ´partement d’Endocrinologie, Diabe ´tologie et Nutrition, Hospices Civils de Lyon, Centre Hos- pitalier Lyon-Sud, F-69530 Pierre-Be ´nite, France; 17 Institut National de la Sante ´ et de la Recherche Me ´dicale Unite ´ 1060, Centre Europe ´ en pour la Nutrition et la Sante ´, Centre de Recherche en Nutrition Humaine Rho ˆne-Alpes, Universite ´ Claude Bernard Lyon, F-69530 Pierre-Be ´nite, France; 18 Service d’Endocri- nologie, Centre Hospitalier Universitaire Co ˆte-de-Nacre, F-14033 Caen, France; 19 Equipe d’Accueil 2608, Universite ´ de Caen-Basse Normandie, F-14032 Caen, France; 20 Unite ´ sous Contrat 2006, Institut National de la Recherche Agronomique, F-14032 Caen, France; 21 De ´partement d’Endocrinologie, Ho ˆpital Haut-Le ´ve ˆque, Centre Hospitalier Universitaire Bordeaux, F-33604 Pessac, France; 22 Service de Biochimie et Hormonologie, Ho ˆpital Tenon, Assistance Pub- lique-Ho ˆpitaux de Paris, F-75020 Paris, France; 23 Laboratoire Commun de Biologie et Ge ´ne ´tique Mole ´culaires, Ho ˆpital Saint-Antoine, Assistance Publique- Ho ˆpitaux de Paris, F-75012 Paris, France; 24 Service de Pe ´diatrie 1, Centre Hospitalier Universitaire Dijon, F-21079 Dijon, France 25 These authors contributed equally to the work *Correspondence: christel.thauvin@chu-dijon.fr (C.T.-R.), jean-baptiste.riviere@u-bourgogne.fr (J.-B.R.) http://dx.doi.org/10.1016/j.ajhg.2013.05.019. Ó2013 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 93, 141–149, July 11, 2013 141