title: Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice.
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.
authors.affiliation: 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.
authors.forename: Adel
authors.initials: A
authors.lastname: Shalata
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ramirez
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Nolan
authors.initials: N
authors.lastname: Priedigkeit
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.forename: Claudia
authors.initials: C
authors.lastname: Lindtner
authors.forename: Mohammed
authors.initials: M
authors.lastname: Mahroum
authors.forename: Muhammad
authors.initials: M
authors.lastname: Abdul-Ghani
authors.forename: Feng
authors.initials: F
authors.lastname: Dong
authors.forename: Nazik
authors.initials: N
authors.lastname: Arar
authors.forename: Olga
authors.initials: O
authors.lastname: Camacho-Vanegas
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Camacho
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Mwafaq
authors.initials: M
authors.lastname: Ibdah
authors.forename: Ralph
authors.initials: R
authors.lastname: DeFronzo
authors.forename: Virginia
authors.initials: V
authors.lastname: Gillespie
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelley
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dynlacht
authors.forename: Sehyun
authors.initials: S
authors.lastname: Kim
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Glucksman
authors.forename: Zvi U
authors.initials: ZU
authors.lastname: Borochowitz
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D003001:Cloning, Molecular; D003241:Consanguinity; D017124:Conserved Sequence; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D020868:Gene Silencing; D018390:Gene Targeting; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009767:Obesity, Morbid / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C586299:CEP19 protein, human; C586300:CEP19 protein, mouse; D018797:Cell Cycle Proteins; D007328:Insulin