Truncating homozygous mutation of carboxypeptidase E (CPE) in a morbidly obese female with type 2 diabetes mellitus, intellectual disability and hypogonadotrophic hypogonadism
S. I. M. Alsters; A. P. Goldstone; J. L. Buxton; A. Zekavati; A. Sosinsky; A. M. Yiorkas; S. Holder; R. E. Klaber; N. Bridges; M. M. Van Haelst; C. W. L. Roux; A. J. Walley; R. G. Walters; M. Mueller; A. I. F. Blakemore
Year of publication
Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76-98del; p. E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.