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Biallelic Mutations in P4HTM Cause Syndromic Obesity.
Sadia Saeed1,2,3, Lijiao Ning2,3, Alaa Badreddine2,3
1Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K.
Diabetes
|April 21, 2023
Summary
A new genetic cause of severe childhood obesity, P4HTM deficiency, has been identified. This recessive condition, linked to mutations in the P4HTM gene, presents with developmental issues and high mortality in affected children.
Area of Science:
- Genetics
- Pediatrics
- Metabolic Disorders
Background:
- 50% of Pakistani children with obesity from consanguineous families have pathogenic variants in known monogenic obesity genes.
- Severe childhood obesity often has a complex genetic basis, with potential for novel gene discovery.
Purpose of the Study:
- To identify novel genetic causes of severe childhood obesity.
- To investigate the role of P4HTM gene variants in syndromic obesity.
Main Methods:
- Whole-exome sequencing of 366 children with severe obesity.
- Computational analysis prioritizing rare homozygous variants.
- Molecular dynamics simulations to assess mutation impact.
Main Results:
- Identified five rare/novel homozygous missense mutations in P4HTM in five consanguineous families.
- Found additional P4HTM mutations in children with obesity from Indian and Moroccan origins.
- P4HTM mutations destabilized the protein's active conformation, leading to syndromic obesity with hypotonia, cognitive impairment, and high mortality.
Conclusions:
- P4HTM deficiency represents a novel form of syndromic obesity.
- This deficiency affects 1.5% of children with obesity in the studied cohort and is associated with significant mortality.
- The role of P4H-TM in energy homeostasis requires further investigation.
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