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  • Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription.

Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription.

Cell metabolism (2020-06-04)
Gaëlle Marenne, Audrey E Hendricks, Aliki Perdikari, Rebecca Bounds, Felicity Payne, Julia M Keogh, Christopher J Lelliott, Elana Henning, Saad Pathan, Sofie Ashford, Elena G Bochukova, Vanisha Mistry, Allan Daly, Caroline Hayward, Nicholas J Wareham, Stephen O'Rahilly, Claudia Langenberg, Eleanor Wheeler, Eleftheria Zeggini, I Sadaf Farooqi, Inês Barroso
ABSTRACT

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability.

MATERIALS
Product Number
Brand
Product Description

Roche
cOmplete, Mini Protease Inhibitor Cocktail, Tablets provided in a glass vial
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Bovine Serum Albumin, heat shock fraction, pH 7, ≥98%
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Penicillin-Streptomycin, with 10,000 units penicillin and 10 mg streptomycin per mL in 0.9% NaCl, 0.1 μm filtered, BioReagent, suitable for cell culture
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Insulin solution human, sterile-filtered, BioXtra, suitable for cell culture
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Dulbecco′s Modified Eagle′s Medium - low glucose, With 1000 mg/L glucose, L-glutamine, and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
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Leptin, Human, Recombinant, E. coli