A Founder Mutation in the POMC 5′-UTR Causes Proopiomelanocortin Deficiency Through Splicing-Mediated Decrease of mRNA

The study identified a novel homozygous mutation in the 5′-UTR of the POMC gene in 7 unrelated patients of Perm Tatar descent, leading to proopiomelanocortin deficiency. This mutation, located at the splice donor site of intron 1, resulted in a significant decrease in POMC mRNA levels, causing symptoms such as hypoglycemia, excessive weight gain, low plasma adrenocorticotropin, cortisol levels, and red hair, with 6 out of 7 patients also experiencing bronchial obstruction. The mutation was suggested to have arisen from a founder effect at least 4.27 generations ago. The study provided insights into the molecular mechanisms and phenotypic variability of POMC deficiency, highlighting a potential novel mechanism for distant 5′-UTR splice-site mutations affecting mRNA expression.