American Diabetes Association
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Biallelic mutations in P4HTM cause syndromic obesity

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posted on 2023-04-21, 15:35 authored by 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

 We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carried 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. This included analysis of whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistani PROMIS study, and 200K participants of the UK Biobank, to prioritize genes harbouring 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 ~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. 


This work was supported by funding from the Medical Research Council (MRC) MR/S026193/1 (P.F.) and the Pakistan Academy of Sciences (M.A). This research has been conducted using the UK Biobank Application #67575. We thank “France Génomique” consortium (ANR-10-INBS-009). This study was funded by the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes] to PF and AB), the French National Research Agency (ANR-10-EQPX-07-01 [LIGAN-PM] to PF and AB), the European Research Council (ERC GEPIDIAB – 294785, to PF; ERC Reg-Seq – 715575, to AB) and the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL). Additional support was provided by the Natural Sciences and Engineering Research Council of Canada (DG-2018-06338).