Summary
This paper reports a monogenic cause of severe childhood obesity: a heterozygous tandem duplication at the ASIP locus that places the agouti signaling protein gene under control of an ubiquitously active promoter, resulting in ectopic ASIP expression across all tissues and germ layers. The phenotype observed in patients—early-onset obesity, overgrowth, red hair and hyperinsulaemia—parallels that of mutant mice expressing the homologous nonagouti gene. By rescreening a large childhood obesity cohort, the authors identified four additional patients with the identical mutation, indicating this aberrant ASIP expression is a recurrent monogenic cause of human obesity.
Regional applicability
This study was conducted in Germany using a German-based childhood obesity cohort. Whilst the genetic findings are applicable internationally given that human genetic variation is largely shared across European populations, translation to United Kingdom clinical practice would require validation in British paediatric obesity populations and assessment of prevalence in UK genetic screening cohorts.
Key measures
ASIP gene expression patterns in patient-derived pluripotent stem cells and hypothalamic-like neurons; phenotypic features (body weight, height, hair colour, insulin levels); prevalence of identical mutation in Leipzig Childhood Obesity cohort (n=1,745)
Outcomes reported
The study identified a heterozygous tandem duplication at the ASIP gene locus causing ubiquitous ectopic ASIP expression in patients with severe early-onset childhood obesity. Five patients total were identified with the identical mutation, ectopic ASIP expression, and a phenotype including obesity, overgrowth, red hair, and hyperinsulaemia.
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