Sadia Saeed1, Amélie Bonnefond2,3,4, Jaida Manzoor5, Faiza Shabbir6, Hina Ayesha7, Julien Philippe2,3,4, Emmanuelle Durand2,3,4, Hutokshi Crouch1, Olivier Sand2,3,4, Muhammad Ali8, Taeed Butt9, Ahsan W Rathore5, Mario Falchi1, Muhammad Arslan6,10, Philippe Froguel1,2,3,4. 1. Department of Genomics of Common Disease, Imperial College London, London, UK. 2. European Genomic Institute for Diabetes (EGID), Lille, France. 3. CNRS-Umr8199, Lille Pasteur Institute, Lille, France. 4. Lille University, Lille, France. 5. Department of Paediatric Endocrinology, Children's Hospital, Lahore, Pakistan. 6. Department of Biological Sciences, Forman Christian College, Lahore, Pakistan. 7. Department of Paediatrics, Punjab Medical College, Faisalabad, Pakistan. 8. Department of Paediatrics, Mayo Hospital, King Edward Medical University, Lahore, Pakistan. 9. Department of Paediatrics, Fatima Memorial Hospital, Lahore, Pakistan. 10. Centre for Research in Molecular Medicine, the University of Lahore, Lahore, Pakistan.
Abstract
OBJECTIVE: Single gene mutations leading to severe obesity have so far been identified in 3-5% cases in European populations. However, prevalence of these pathogenic mutations has not systematically been examined in specific consanguineous populations. Here we describe the incidence of obesity-associated mutations through a step-wise sequence analysis, in a cohort of 73 Pakistani children with severe obesity from consanguineous families. METHODS: Initially, all subjects were screened for mutations in coding regions of leptin (LEP) and melanocortin 4 receptor (MC4R) genes by direct sequencing. Subjects negative for mutation in these genes were screened using microdroplet PCR enrichment and NGS. Genomic structural variation was assessed by genotyping. Serum leptin, insulin, and cortisol were determined by ELISA. RESULTS: Among 73 children with severe obesity (BMI SDS > 3.0), we identified 22 probands and 5 relatives, carrying 10 different loss-of-function homozygous mutations in LEP, leptin receptor (LEPR), and MC4R genes, including 4 novel variants. Hypercortisolemia was significantly emphasized in LEP mutation carriers. CONCLUSIONS: The prevalence of pathogenic mutations in genes known to directly influence leptin-melanocortin signaling is 30% in our cohort. The results of this study emphasize the desirability of undertaking systematic and in-depth genetic analysis of cases with severe obesity in specific consanguineous populations.
OBJECTIVE: Single gene mutations leading to severe obesity have so far been identified in 3-5% cases in European populations. However, prevalence of these pathogenic mutations has not systematically been examined in specific consanguineous populations. Here we describe the incidence of obesity-associated mutations through a step-wise sequence analysis, in a cohort of 73 Pakistani children with severe obesity from consanguineous families. METHODS: Initially, all subjects were screened for mutations in coding regions of leptin (LEP) and melanocortin 4 receptor (MC4R) genes by direct sequencing. Subjects negative for mutation in these genes were screened using microdroplet PCR enrichment and NGS. Genomic structural variation was assessed by genotyping. Serum leptin, insulin, and cortisol were determined by ELISA. RESULTS: Among 73 children with severe obesity (BMI SDS > 3.0), we identified 22 probands and 5 relatives, carrying 10 different loss-of-function homozygous mutations in LEP, leptin receptor (LEPR), and MC4R genes, including 4 novel variants. Hypercortisolemia was significantly emphasized in LEP mutation carriers. CONCLUSIONS: The prevalence of pathogenic mutations in genes known to directly influence leptin-melanocortin signaling is 30% in our cohort. The results of this study emphasize the desirability of undertaking systematic and in-depth genetic analysis of cases with severe obesity in specific consanguineous populations.
Authors: Claudia Terezia Socol; Alexandra Chira; Maria Antonia Martinez-Sanchez; Maria Angeles Nuñez-Sanchez; Cristina Maria Maerescu; Daniel Mierlita; Alexandru Vasile Rusu; Antonio Jose Ruiz-Alcaraz; Monica Trif; Bruno Ramos-Molina Journal: Int J Mol Sci Date: 2022-04-24 Impact factor: 6.208
Authors: Lon Phan; Jeffrey Hsu; Le Quang Minh Tri; Michaela Willi; Tamer Mansour; Yan Kai; John Garner; John Lopez; Ben Busby Journal: F1000Res Date: 2016-04-13
Authors: Niels Vos; Sabrina M Oussaada; Mellody I Cooiman; Lotte Kleinendorst; Kasper W Ter Horst; Eric J Hazebroek; Johannes A Romijn; Mireille J Serlie; Marcel M A M Mannens; Mieke M van Haelst Journal: Curr Diab Rep Date: 2020-07-30 Impact factor: 4.810