ARTICLE Morbid Obesity Resulting from Inactivation of the Ciliary Protein CEP19 in Humans and Mice Adel Shalata, 1,7,8, * Maria C. Ramirez, 1 Robert J. Desnick, 1 Nolan Priedigkeit, 1 Christoph Buettner, 2 Claudia Lindtner, 2 Mohammed Mahroum, 7 Muhammad Abdul-Ghani, 9 Feng Dong, 9 Nazik Arar, 9 Olga Camacho-Vanegas, 1 Rui Zhang, 1 Sandra C. Camacho, 1 Ying Chen, 1 Mwafaq Ibdah, 7 Ralph DeFronzo, 9 Virginia Gillespie, 5 Kevin Kelley, 6 Brian D. Dynlacht, 10 Sehyun Kim, 10 Marc J. Glucksman, 11 Zvi U. Borochowitz, 7,12 and John A. Martignetti 1,3,4, * Obesity is a major public health concern, and complementary research strategies have been directed toward the identification of the underlying causative gene mutations that affect the normal pathways and networks that regulate energy balance. Here, we describe an autosomal-recessive morbid-obesity syndrome and identify the disease-causing gene defect. The average body mass index of affected family members was 48.7 (range ¼ 36.7–61.0), and all had features of the metabolic syndrome. Homozygosity mapping localized the disease locus to a region in 3q29; we designated this region the morbid obesity 1 (MO1) locus. Sequence analysis identified a homozy- gous nonsense mutation in CEP19, the gene encoding the ciliary protein CEP19, in all affected family members. CEP19 is highly conserved in vertebrates and invertebrates, is expressed in multiple tissues, and localizes to the centrosome and primary cilia. Homozy- gous Cep19-knockout mice were morbidly obese, hyperphagic, glucose intolerant, and insulin resistant. Thus, loss of the ciliary protein CEP19 in humans and mice causes morbid obesity and defines a target for investigating the molecular pathogenesis of this disease and potential treatments for obesity and malnutrition. Introduction Obesity is a major risk factor for type II diabetes mellitus (T2DM), heart disease, hypertension, metabolic syndrome, and cancer, and it has become increasingly prevalent in Western society and in developing countries. 1 Worldwide, more than 1.1 billion individuals are overweight and more than 300 million are obese, 2 as assessed by body mass index (BMI). Individuals with a BMI R 30 kg/m 2 are con- sidered obese, whereas those with a BMI > 40 are morbidly obese. The importance of genetic factors in human obesity have been clearly defined by numerous twin, familial- aggregation, and adoption studies. 3–6 Indeed, heritability has been estimated to be as high as 40%–90%. 7 Given this relationship, a number of genetic approaches have been used in the search for the genes and pathways affecting BMI. 8 Genome-wide association studies (GWASs), using either population-based cohorts or case-control de- signs, have identified numerous candidate-gene loci; how- ever, most loci have only modest effects. What has become readily apparent is that biologically plausible candidate genes within these regions are not always intuitively obvious and thus might go undetected. In contrast, targeted molecular analysis of Mendelian obesity disorders has provided unambiguous identifica- tion of causative gene mutations, providing insights into the pathogenetic mechanisms underlying obesity. 9 Here, we describe a consanguineous multigenerational Israeli Arab family affected by autosomal-recessive morbid obesity, which we have designated ‘‘MO1 syndrome.’’ Linkage analysis and positional gene cloning identified a truncating mutation in a highly evolutionarily conserved gene within the MO1 locus; this gene, CEP19, was recently found to encode CEP19, a ciliary protein. 10 Targeted knockout (KO) of Cep19 resulted in markedly obese mice exhibiting hyperphagia, decreased energy expenditure, impaired whole-body fat oxidation, altered hepatic insulin signaling, and impaired glucose and insu- lin tolerance. Material and Methods Study Subjects This study investigated members of a multigenerational Arab clan living in the same village in the north of Israel. After informed consent was obtained and approval was received from the ethics committees of the corresponding institutions, blood samples were drawn from 13 affected and 31 unaffected family members. Clinical diagnoses were provided by the referring physicians. 1 Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA; 2 Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA; 3 Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA; 4 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA; 5 Center for Comparative Medicine and Surgery, Mount Sinai School of Medicine, New York, NY 10029, USA; 6 Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA; 7 Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, 31048 Haifa, Israel; 8 Clalit Health Services Group, 30810 Sakhnin City, Israel; 9 Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; 10 Department of Pathology, School of Medicine, New York University Cancer Institute, New York, NY 10016, USA; 11 Midwest Proteome Center and Department of Biochemistry and Molecular Biology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL 60064, USA; 12 The Rappaport Faculty of Medicine and Research Institute, Technion – Israel Institute of Technology, 31096 Haifa, Israel *Correspondence: adelsh@clalit.org.il (A.S.), john.martignetti@mssm.edu (J.A.M.) http://dx.doi.org/10.1016/j.ajhg.2013.10.025. Ó2013 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 93, 1061–1071, December 5, 2013 1061