Authors
Sadia Saeed, 1Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K. 2INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, FranceFollow
Lijiao Ning, 2INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Alaa Badreddine, 2INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Muhammad Usman Mirza, 4Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada
Mathilde Boissel, 1Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K. 2INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Roohia Khanam, School of Life Sciences, Forman Christian College, Lahore, Pakistan
Jaida Manzoor, Department of Paediatric Endocrinology, Children’s Hospital, Lahore, Pakistan
Qasim M. Janjua, Department of Physiology and Biophysics, National University of Science and Technology, Sohar, Oman
Waqas I. Khan, The Children Hospital and the Institute of Child Health, Multan, Pakistan
Bénédicte Toussaint, INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Emmanuel Vaillant, INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Souhila Amanzougarene, INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Mehdi Derhourhi, INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
John F. Trant, Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada
Anna-Maria Siegert, Medical Research Council Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, U.K
Brian Y.H. Lam, Medical Research Council Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, U.K.
Giles S.H. Yeo, Medical Research Council Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, U.K.
Layachi Chabraoui, Laboratory of Biochemistry and Molecular Biology, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
Asmae Touzani, Children’s Hospital of Rabat and Laboratory of Biochemistry and Molecular Biology, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
Abhishek Kulkarni, Department of Paediatric Endocrinology, Sir H. N. Reliance Foundation, SRCC Children’s Hospital, Mumbai, India
I. Sadaf Farooqi, Medical Research Council Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, U.K.
Amélie Bonnefond, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K. 2INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, France
Muhammad Arslan, School of Life Sciences, Forman Christian College, Lahore, Pakistan
Philippe Froguel, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K. 2INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France 3University of Lille, Lille University Hospital, Lille, FranceFollow
Author ORCID Identifier
https://orcid.org/0000-0002-4780-4968 : John Trant
Publication Title
Diabetes
Abstract
We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.
DOI
https://doi.org/10.2337/db22-1017
Recommended Citation
Saeed, Sadia; Ning, Lijiao; Badreddine, Alaa; Mirza, Muhammad Usman; Boissel, Mathilde; Khanam, Roohia; Manzoor, Jaida; Janjua, Qasim M.; Khan, Waqas I.; Toussaint, Bénédicte; Vaillant, Emmanuel; Amanzougarene, Souhila; Derhourhi, Mehdi; Trant, John F.; Siegert, Anna-Maria; Lam, Brian Y.H.; Yeo, Giles S.H.; Chabraoui, Layachi; Touzani, Asmae; Kulkarni, Abhishek; Farooqi, I. Sadaf; Bonnefond, Amélie; Arslan, Muhammad; and Froguel, Philippe. (2023). Biallelic Mutations in P4HTM Cause Syndromic Obesity. Diabetes, 2023 (72), 1228-1234.
https://scholar.uwindsor.ca/chemistrybiochemistrypub/342
Comments
Sadia Saeed, Lijiao Ning, Alaa Badreddine, Muhammad Usman Mirza, Mathilde Boissel, Roohia Khanam, Jaida Manzoor, Qasim M. Janjua, Waqas I. Khan, Bénédicte Toussaint, Emmanuel Vaillant, Souhila Amanzougarene, Mehdi Derhourhi, John F. Trant, Anna-Maria Siegert, Brian Y.H. Lam, Giles S.H. Yeo, Layachi Chabraoui, Asmae Touzani, Abhishek Kulkarni, I. Sadaf Farooqi, Amélie Bonnefond, Muhammad Arslan, Philippe Froguel; Biallelic Mutations in P4HTM Cause Syndromic Obesity. Diabetes 1 September 2023; 72 (9): 1228–1234. https://doi.org/10.2337/db22-1017