Publications
26 results found
Saeed S, Khanam R, Janjua QM, et al., 2023, High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor, CELL REPORTS MEDICINE, Vol: 4, ISSN: 2666-3791
Saeed S, Ning L, Badreddine A, et al., 2023, Biallelic Mutations in P4HTM Cause Syndromic Obesity., Diabetes, Vol: 72, Pages: 1228-1234
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.
Talbot F, Feetham CH, Mokrosinski J, et al., 2023, A rare human variant that disrupts GPR10 signalling causes weight gain in mice, NATURE COMMUNICATIONS, Vol: 14
Saeed S, Manzoor J, Khanam R, et al., 2022, Natural History of LEP, LEPR and MC4R Deficiencies - A Population-Based Study, Publisher: KARGER, Pages: 35-36, ISSN: 1663-2818
Saeed S, Janjua QM, Haseeb A, et al., 2022, Rare variant analysis of obesity associated genes in young adults from a consanguineous population of Pakistan, 54th Conference of the European-Society-of-Human-Genetics (ESHG), Publisher: SPRINGERNATURE, Pages: 441-441, ISSN: 1018-4813
Saeed S, Janjua QM, Haseeb A, et al., 2022, Rare Variant Analysis of Obesity-Associated Genes in Young Adults With Severe Obesity From a Consanguineous Population of Pakistan, DIABETES, Vol: 71, Pages: 694-705, ISSN: 0012-1797
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- Citations: 4
Saeed S, Arslan M, Manzoor J, et al., 2020, Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan, DIABETES, Vol: 69, Pages: 1424-1438, ISSN: 0012-1797
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- Citations: 14
Saeed S, Arslan M, Froguel P, 2018, Genetics of Obesity in Consanguineous Populations: Toward Precision Medicine and the Discovery of Novel Obesity Genes, OBESITY, Vol: 26, Pages: 474-484, ISSN: 1930-7381
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- Citations: 20
Saeed S, Bonnefond A, Tamanini F, et al., 2018, Loss-of-function mutations in ADCY3 cause monogenic severe obesity, NATURE GENETICS, Vol: 50, Pages: 175-179, ISSN: 1061-4036
Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin–melanocortin pathway in controlling energy balance, appetite and body weight1. The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin–melanocortin signaling. These genes, however, only explain obesity in <5% of cases, predominantly from outbred populations2. We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity3,4,5. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the ADCY3 gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.
Saeed S, Bonnefond A, Manzoor J, et al., 2017, Genetic Variants in LEP, LEPR, and MC4R Explain 30% of Severe Obesity in Children from a Consanguineous Population (vol 23, pg 1687, 2015), OBESITY, Vol: 25, Pages: 807-807, ISSN: 1930-7381
Janjua QM, Shahid A, Alam R, et al., 2015, Evidence of male hypogonadism at an early age as a familial risk of type 2 diabetes, ANNALES D ENDOCRINOLOGIE, Vol: 76, Pages: 658-663, ISSN: 0003-4266
Saeed S, Bonnefond A, Manzoor J, et al., 2015, Genetic variants in <i>LEP</i>, <i>LEPR</i>, and <i>MC4R</i> explain 30% of severe obesity in children from a consanguineous population, OBESITY, Vol: 23, Pages: 1687-1695, ISSN: 1930-7381
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- Citations: 59
Pearce LR, Joe R, Doche ME, et al., 2014, Functional Characterization of Obesity-Associated Variants Involving the α and β Isoforms of Human SH2B1, ENDOCRINOLOGY, Vol: 155, Pages: 3219-3226, ISSN: 0013-7227
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- Citations: 26
Ghani A, Ali Z, Islam T, et al., 2014, Nutrient evaluation and elemental analysis of four selected medicinal plants of soon valley Khushab, Punjab, Pakistan, PAKISTAN JOURNAL OF PHARMACEUTICAL SCIENCES, Vol: 27, Pages: 597-600, ISSN: 1011-601X
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- Citations: 4
Saeed S, Bech PR, Hafeez T, et al., 2014, Changes in levels of peripheral hormones controlling appetite are inconsistent with hyperphagia in leptin-deficient subjects, ENDOCRINE, Vol: 45, Pages: 401-408, ISSN: 1355-008X
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- Citations: 14
Saeed S, Bonnefond A, Manzoor J, et al., 2014, Novel LEPR Mutations in Obese Pakistani Children Identified by PCR-Based Enrichment and Next Generation Sequencing, OBESITY, Vol: 22, Pages: 1112-1117, ISSN: 1930-7381
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- Citations: 37
Bonnefond A, Philippe J, Durand E, et al., 2014, Highly Sensitive Diagnosis of 43 Monogenic Forms of Diabetes or Obesity Through One-Step PCR-Based Enrichment in Combination With Next-Generation Sequencing, DIABETES CARE, Vol: 37, Pages: 460-467, ISSN: 0149-5992
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- Citations: 57
Saeed S, Butt TA, Anwer M, et al., 2013, High prevalence of leptin and melanocotin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families (vol 106, pg 121, 2012), MOLECULAR GENETICS AND METABOLISM, Vol: 109, Pages: 404-404, ISSN: 1096-7192
Ramachandrappa S, Raimondo A, Cali AMG, et al., 2013, Rare variants in single-minded 1 (<i>SIM1</i>) are associated with severe obesity (vol 123, pg 3042, 2013), JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 3635-3635, ISSN: 0021-9738
Ramachandrappa S, Raimondo A, Cali AMG, et al., 2013, Rare variants in single-minded 1 (<i>SIM1</i>) are associated with severe obesity, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 3042-3050, ISSN: 0021-9738
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- Citations: 98
Doche ME, Bochukova EG, Su HW, et al., 2013, Erratum: Human SH2B1 mutations are associated with maladaptive behaviors and obesity (Journal of Clinical Investigation (2013) 123:1 (526) DOI: 10.1172/JCI68022), Journal of Clinical Investigation, Vol: 123, ISSN: 0021-9738
Doche ME, Bochukova EG, Su H-W, et al., 2012, Human SH2B1 mutations are associated with maladaptive behaviors and obesity, Journal of Clinical Investigation, Vol: 122, Pages: 4732-4736, ISSN: 0021-9738
Saeed S, Butt TA, Anwer M, et al., 2012, High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families, MOLECULAR GENETICS AND METABOLISM, Vol: 106, Pages: 121-126, ISSN: 1096-7192
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- Citations: 54
Shahid A, Saeed S, Saeed S, et al., 2011, EVIDENCE OF HYPOGONADISM AND ITS ASSOCIATION WITH SERUM INSULIN AND LEPTIN LEVELS IN MALE OFFSPRING OF DIABETIC PARENTS, ACTA ENDOCRINOLOGICA-BUCHAREST, Vol: 7, Pages: 365-372, ISSN: 1841-0987
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- Citations: 1
Bochukova EG, Huang N, Keogh J, et al., 2010, Large, rare chromosomal deletions associated with severe early-onset obesity, NATURE, Vol: 463, Pages: 666-670, ISSN: 0028-0836
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- Citations: 376
Shahid A, Lone KP, Saeed S, et al., 2008, Male offspring of both diabetic parents have higher insulin resistance and serum leptin levels compared to those with one diabetic parent, HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM, Vol: 7, Pages: 313-319, ISSN: 1109-3099
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- Citations: 17
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