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Genes 2014, 5(3), 709-725; doi:10.3390/genes5030709

Whole Exome Sequencing of Extreme Morbid Obesity Patients: Translational Implications for Obesity and Related Disorders

1
Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia
2
Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Avenida Agostinho Leão Junior, 285-Alto da Glória. CEP 80030-110, Curitiba-PR, Brazil
3
Mind and Brain Theme, South Australian Health and Medical Research Institute, and Department of Psychiatry, School of Medicine, Flinders University, PO Box 11060 Adelaide SA 5001, Adelaide, Australia
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 13 May 2014 / Revised: 23 July 2014 / Accepted: 14 August 2014 / Published: 25 August 2014
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Abstract

Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female child with severe early-onset obesity. Additionally, the teenager patient had hypopituitarism and hyperprolactinaemia. A comprehensive bioinformatics analysis found de novo and compound heterozygote sequence variants with a damaging effect on genes previously associated with obesity in mice (LRP2) and humans (UCP2), among other intriguing mutations affecting ciliary function (DNAAF1). A gene ontology and pathway analysis of genes harbouring mutations resulted in the significant identification of overrepresented pathways related to ATP/ITP (adenosine/inosine triphosphate) metabolism and, in general, to the regulation of lipid metabolism. We discuss the clinical and physiological consequences of these mutations and the importance of these findings for either the clinical assessment or eventual treatment of morbid obesity. View Full-Text
Keywords: DNAAF1; genetics; leptin-melanocortin; LRP2; megalin; monogenic; obesity; pituitary; UCP2; whole-exome sequencing DNAAF1; genetics; leptin-melanocortin; LRP2; megalin; monogenic; obesity; pituitary; UCP2; whole-exome sequencing
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Paz-Filho, G.; Boguszewski, M.C.; Mastronardi, C.A.; Patel, H.R.; Johar, A.S.; Chuah, A.; Huttley, G.A.; Boguszewski, C.L.; Wong, M.-L.; Arcos-Burgos, M.; Licinio, J. Whole Exome Sequencing of Extreme Morbid Obesity Patients: Translational Implications for Obesity and Related Disorders. Genes 2014, 5, 709-725.

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