2. Academic Validation
  3. Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice

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

  • Am J Hum Genet. 2013 Dec 5;93(6):1061-71. doi: 10.1016/j.ajhg.2013.10.025.
Adel Shalata 1,  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 Kim,  Marc J Glucksman,  Zvi U Borochowitz,  John A Martignetti
Affiliations

Affiliation

  • 1 Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA; Simon Winter Institute for Human Genetics, Bnai-Zion Medical Center, 31048 Haifa, Israel; Clalit Health Services Group, 30810 Sakhnin City, Israel. Electronic address: adelsh@clalit.org.il.
PMID: 24268657 DOI: 10.1016/j.ajhg.2013.10.025
Abstract

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.

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