Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice

Adel Shalata, Maria C. Ramirez, Robert J. Desnick, Nolan Priedigkeit, Christoph Buettner, Claudia Lindtner, Mohammed Mahroum, Muhammad Abdul-Ghani, Feng Dong, Nazik Arar, Olga Camacho-Vanegas, Rui Zhang, Sandra C. Camacho, Ying Chen, Mwafaq Ibdah, Ralph Defronzo, Virginia Gillespie, Kevin Kelley, Brian D. Dynlacht, Sehyun KimMarc J. Glucksman, Zvi U. Borochowitz, John A. Martignetti

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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 = 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 homozygous 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. Homozygous 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.

Original languageEnglish
Pages (from-to)1061-1071
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - 5 Dec 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank all the family members who participated in this study. J.A.M. was supported in part by a National Institutes of Health (NIH) grant (5R01DK071298), B.D.D. was supported by a March of Dimes award and by an NIH grant (5 R01 HD069647), and M.A.G. received financial support through an American Heart Association grant (10SDG4470014). J.A.M. would like to thank A. Cederbaum, C. Mobbs, and D. Leroith for their thoughtful and critical advice throughout these studies. A.S. thanks A. Ahronhiem for his generous advice and fruitful discussions of the mouse research.


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