PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.

Abstract

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous 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 retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α 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.

• Authors: 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
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 93 Issue 1 Pg. 141-9 (Jul 11 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 23810378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Insulin
• Phosphatidylinositol 3-Kinases
• AKT2 protein, human
• Proto-Oncogene Proteins c-akt
• Glucose

Topics

• DNA Mutational Analysis
• Exome
• Female
• Fibroblasts (drug effects, metabolism, pathology)
• Genetic Predisposition to Disease
• Gestational Age
• Glucose (metabolism, pharmacology)
• Growth Disorders (genetics)
• Humans
• Hypercalcemia (genetics)
• Insulin (metabolism, pharmacology)
• Insulin Resistance (genetics)
• Male
• Metabolic Diseases (genetics)
• Mutation
• Nephrocalcinosis (genetics)
• Pedigree
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction