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 Kim; Marc J. Glucksman; Zvi U. Borochowitz; John A. Martignetti

doi:10.1016/j.ajhg.2013.10.025

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

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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.

Original language	English
Pages (from-to)	1061-1071
Number of pages	11
Journal	American Journal of Human Genetics
Volume	93
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2013.10.025
State	Published - 5 Dec 2013
Externally published	Yes

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.

Funding

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.

Funders	Funder number
National Institutes of Health	5R01DK071298
National Institute of Child Health and Human Development	R01HD069647
March of Dimes Foundation	5 R01 HD069647
American Heart Association	10SDG4470014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2013.10.025

Cite this

Shalata, A., Ramirez, M. C., Desnick, R. J., Priedigkeit, N., Buettner, C., Lindtner, C., Mahroum, M., Abdul-Ghani, M., Dong, F., Arar, N., Camacho-Vanegas, O., Zhang, R., Camacho, S. C., Chen, Y., Ibdah, M., Defronzo, R., Gillespie, V., Kelley, K., Dynlacht, B. D., ... Martignetti, J. A. (2013). Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice. American Journal of Human Genetics, 93(6), 1061-1071. https://doi.org/10.1016/j.ajhg.2013.10.025

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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.",

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

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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Shalata, A, Ramirez, MC, Desnick, RJ, Priedigkeit, N, Buettner, C, Lindtner, C, Mahroum, M, Abdul-Ghani, M, Dong, F, Arar, N, Camacho-Vanegas, O, Zhang, R, Camacho, SC, Chen, Y, Ibdah, M, Defronzo, R, Gillespie, V, Kelley, K, Dynlacht, BD, Kim, S, Glucksman, MJ, Borochowitz, ZU & Martignetti, JA 2013, 'Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice', American Journal of Human Genetics, vol. 93, no. 6, pp. 1061-1071. https://doi.org/10.1016/j.ajhg.2013.10.025

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T1 - Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice

AU - Shalata, Adel

AU - Ramirez, Maria C.

AU - Desnick, Robert J.

AU - Priedigkeit, Nolan

AU - Buettner, Christoph

AU - Lindtner, Claudia

AU - Mahroum, Mohammed

AU - Abdul-Ghani, Muhammad

AU - Dong, Feng

AU - Arar, Nazik

AU - Camacho-Vanegas, Olga

AU - Zhang, Rui

AU - Camacho, Sandra C.

AU - Chen, Ying

AU - Ibdah, Mwafaq

AU - Defronzo, Ralph

AU - Gillespie, Virginia

AU - Kelley, Kevin

AU - Dynlacht, Brian D.

AU - Kim, Sehyun

AU - Glucksman, Marc J.

AU - Borochowitz, Zvi U.

AU - Martignetti, John A.

N1 - 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.

PY - 2013/12/5

Y1 - 2013/12/5

N2 - 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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Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice

Abstract

Bibliographical note

Funding

UN SDGs

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