Exploring Autosomal Dominant Non-Syndromic Monogenic Obesity: From Genes to Therapy

Area of Science:

• Genetics
• Endocrinology
• Metabolic Diseases

Background:

• Genetic factors significantly influence obesity pathophysiology by regulating energy homeostasis.
• Monogenic non-syndromic obesity, caused by mutations in the leptin-melanocortin pathway genes, accounts for 2-3% of obesity cases.
• Genetic testing is recommended for children with early-onset severe obesity, hyperphagia, family history, and developmental or organ issues.

Purpose of the Study:

• To provide a comprehensive review of autosomal dominant forms of monogenic non-syndromic obesity.
• To analyze the genetic and molecular characteristics of these conditions.
• To examine clinical presentations and explore therapeutic strategies.

Main Methods:

• Review of genetic mutations and inheritance patterns (autosomal recessive and dominant).
• Analysis of genes involved in the leptin-melanocortin pathway.
• Evaluation of clinical phenotypes, penetrance, and gene-environment interactions.

Main Results:

• Monogenic obesity involves mutations in genes like LEP, LEPR, POMC, PCSK1 (recessive), and MC4R, SH2B1, SIM1, GNAS (dominant).
• Other genes (MRAP2, MC3R, SRC1, KSR2) in heterozygous states can also cause obesity with dominant inheritance patterns.
• Currently, no targeted pharmacotherapies exist for autosomal dominant monogenic obesity, and diagnostic confirmation is often delayed by variants of uncertain significance.

Conclusions:

• Autosomal dominant monogenic obesity presents complex genetic and clinical challenges.
• Further research is needed to develop effective therapeutic strategies for these specific genetic forms of obesity.
• Accurate genetic diagnosis is essential for understanding disease mechanisms and guiding patient management.