{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:18:57Z","timestamp":1791188337558,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2014,8,25]],"date-time":"2014-08-25T00:00:00Z","timestamp":1408924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100000995","name":"Australian National University","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100000995","id-type":"DOI","asserted-by":"publisher"}]},{"name":"John James Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes5030709","type":"journal-article","created":{"date-parts":[[2014,8,25]],"date-time":"2014-08-25T11:58:03Z","timestamp":1408967883000},"page":"709-725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Whole Exome Sequencing of Extreme Morbid Obesity Patients: Translational Implications for Obesity and Related Disorders"],"prefix":"10.3390","volume":"5","author":[{"given":"Gilberto","family":"Paz-Filho","sequence":"first","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Boguszewski","sequence":"additional","affiliation":[{"name":"Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Avenida Agostinho Le\u00e3o Junior, 285-Alto da Gl\u00f3ria. CEP 80030-110, Curitiba-PR, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Mastronardi","sequence":"additional","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardip","family":"Patel","sequence":"additional","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angad","family":"Johar","sequence":"additional","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Chuah","sequence":"additional","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Huttley","sequence":"additional","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar","family":"Boguszewski","sequence":"additional","affiliation":[{"name":"Endocrine Division (SEMPR), Department of Internal Medicine, Federal University of Parana, Avenida Agostinho Le\u00e3o Junior, 285-Alto da Gl\u00f3ria. CEP 80030-110, Curitiba-PR, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma-Li","family":"Wong","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Arcos-Burgos","sequence":"additional","affiliation":[{"name":"Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Garran Rd, building 131, Acton, Canberra, ACT 0200, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Licinio","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,8,25]]},"reference":[{"key":"ref_1","unstructured":"WHO Obesity and Overweight. Available online:http:\/\/www.who.int\/mediacentre\/factsheets\/fs311\/en\/index.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrendo.2012.199","article-title":"Global obesity: Trends, risk factors and policy implications","volume":"9","author":"Malik","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1023\/A:1025635913927","article-title":"Genetic and environmental factors in relative body weight and human adiposity","volume":"27","author":"Maes","year":"1997","journal-title":"Behav. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nrendo.2013.57","article-title":"From obesity genetics to the future of personalized obesity therapy","volume":"9","author":"Froguel","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.beem.2011.11.003","article-title":"Genetic determinants of common obesity and their value in prediction","volume":"26","author":"Loos","year":"2012","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1210\/er.2006-0040","article-title":"Genetics of obesity in humans","volume":"27","author":"Farooqi","year":"2006","journal-title":"Endocr. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1126\/science.1233000","article-title":"Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity","volume":"341","author":"Asai","year":"2013","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrg3031","article-title":"Exome sequencing as a tool for mendelian disease gene discovery","volume":"12","author":"Bamshad","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1001\/jamaneurol.2013.247","article-title":"Clinical application of whole-exome sequencing: A novel autosomal recessive spastic ataxia","volume":"70","author":"Liew","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1136\/jmedgenet-2012-100819","article-title":"Clinical application of exome sequencing in undiagnosed genetic conditions","volume":"49","author":"Need","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrg3241","article-title":"De novo mutations in human genetic disease","volume":"13","author":"Veltman","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1056\/NEJMoa1306555","article-title":"Clinical whole-exome sequencing for the diagnosis of mendelian disorders","volume":"369","author":"Yang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/oby.20492","article-title":"Whole-exome sequencing identifies novel lepr mutations in individuals with severe early onset obesity","volume":"22","author":"Gill","year":"2013","journal-title":"Obesity"},{"key":"ref_14","unstructured":"Hendricks, A.E. (2013). Whole Exome Sequencing Case-Control Using 1000 Severe Obesity Cases Identifies Putative New Loci and Replicates Previously Established Loci, American Society of Human Genetics."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1136\/jmedgenet-2013-101785","article-title":"Exome sequencing of bardet-biedl syndrome patient identifies a null mutation in the bbsome subunit bbip1 (bbs18)","volume":"51","author":"Scheidecker","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1038\/ncomms2896","article-title":"Clusterin and lrp2 are critical components of the hypothalamic feeding regulatory pathway","volume":"4","author":"Gil","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/ng0397-269","article-title":"Uncoupling protein-2: A novel gene linked to obesity and hyperinsulinemia","volume":"15","author":"Fleury","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7796","DOI":"10.1073\/pnas.1210192110","article-title":"Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice","volume":"110","author":"Berbari","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/j.1399-0004.2009.01305.x","article-title":"Ciliary dysfunction and obesity","volume":"77","author":"Mok","year":"2010","journal-title":"Clin. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1210\/en.2004-0074","article-title":"Evidence indicating that renal tubular metabolism of leptin is mediated by megalin but not by the leptin receptors","volume":"145","author":"Hama","year":"2004","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.neurobiolaging.2007.01.008","article-title":"Megalin mediates the transport of leptin across the blood-csf barrier","volume":"29","author":"Dietrich","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1073\/pnas.90.2.725","article-title":"Apolipoprotein j expression at fluid-tissue interfaces: Potential role in barrier cytoprotection","volume":"90","author":"Aronow","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/bdra.20534","article-title":"A review of donnai-barrow and facio-oculo-acoustico-renal (db\/foar) syndrome: Clinical features and differential diagnosis","volume":"85","author":"Pober","year":"2009","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1042\/BJ20100779","article-title":"Mutation of megalin leads to urinary loss of selenoprotein p and selenium deficiency in serum, liver, kidneys and brain","volume":"431","author":"Theilig","year":"2010","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/07853890701214881","article-title":"The ldl receptor-related protein (lrp) family: An old family of proteins with new physiological functions","volume":"39","author":"May","year":"2007","journal-title":"Ann. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8460","DOI":"10.1073\/pnas.93.16.8460","article-title":"Defective forebrain development in mice lacking gp330\/megalin","volume":"93","author":"Willnow","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ha, S., Stottmann, R.W., Furley, A.J., and Beier, D.R. (2013). A forward genetic screen in mice identifies mutants with abnormal cortical patterning. Cereb. Cortex.","DOI":"10.1093\/cercor\/bht209"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/ng2063","article-title":"Mutations in lrp2,which encodes the multiligand receptor megalin, cause donnai-barrow and facio-oculo-acoustico-renal syndromes","volume":"39","author":"Kantarci","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1007\/s11695-007-9171-6","article-title":"Ala55val polymorphism on ucp2 gene predicts greater weight loss in morbidly obese patients undergoing gastric banding","volume":"17","author":"Chen","year":"2007","journal-title":"Obes. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1475-2840-11-41","article-title":"Uncoupling protein 2 gene polymorphisms are associated with obesity","volume":"11","author":"Oktavianthi","year":"2012","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/sj.ijo.0801564","article-title":"The association between the val\/ala-55 polymorphism of the uncoupling protein 2 gene and exercise efficiency","volume":"25","author":"Buemann","year":"2001","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1164\/rccm.201301-0059CI","article-title":"Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease","volume":"188","author":"Knowles","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.2337\/diabetes.54.10.3049","article-title":"Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity","volume":"54","author":"Bell","year":"2005","journal-title":"Diabetes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1126\/science.1124147","article-title":"Hypothalamic mtor signaling regulates food intake","volume":"312","author":"Cota","year":"2006","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cub.2007.08.034","article-title":"Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease","volume":"17","author":"Davenport","year":"2007","journal-title":"Curr. Biol. CB"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1073\/pnas.0812518106","article-title":"Transient ciliogenesis involving bardet-biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation","volume":"106","author":"Marion","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1677\/JOE-09-0116","article-title":"Can faulty antennae increase adiposity? The link between cilia proteins and obesity","volume":"203","author":"Prodromou","year":"2009","journal-title":"J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6989","DOI":"10.1523\/JNEUROSCI.1089-09.2009","article-title":"Role of neuroepithelial sonic hedgehog in hypothalamic patterning","volume":"29","author":"Szabo","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_39","unstructured":"British 1958 birth cohort DNA Collection. Available online:http:\/\/www.b58cgene.sgul.ac.uk\/."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/mp.2010.107","article-title":"A genome-wide association study on common snps and rare cnvs in anorexia nervosa","volume":"16","author":"Wang","year":"2011","journal-title":"Mol. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e96411","DOI":"10.1371\/journal.pone.0096411","article-title":"Meta-analysis reveals the association of common variants in the uncoupling protein (ucp) 1\u20133 genes with body mass index variability","volume":"9","author":"Brondani","year":"2014","journal-title":"PLoS One"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e96149","DOI":"10.1371\/journal.pone.0096149","article-title":"Replication of 6 obesity genes in a meta-analysis of genome-wide association studies from diverse ancestries","volume":"9","author":"Tan","year":"2014","journal-title":"PLoS One"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.ajhg.2014.05.003","article-title":"Forge canada consortium: Outcomes of a 2-year national rare-disease gene-discovery project","volume":"94","author":"Beaulieu","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/jhg.2013.114","article-title":"The promise of whole-exome sequencing in medical genetics","volume":"59","author":"Rabbani","year":"2014","journal-title":"J. Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/5\/3\/709\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:15:12Z","timestamp":1760217312000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/5\/3\/709"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,25]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,9]]}},"alternative-id":["genes5030709"],"URL":"https:\/\/doi.org\/10.3390\/genes5030709","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,25]]}}}