Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism

Suzanne I M Alsters, Anthony P Goldstone, Jessica L Buxton, Anna Zekavati, Alona Sosinsky, Andrianos M Yiorkas, Susan Holder, Robert E Klaber, Nicola Bridges, Mieke M van Haelst, Carel W le Roux, Andrew J Walley, Robin G Walters, Michael Mueller, Alexandra I F Blakemore

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51 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)e0131417
Issue number6
Publication statusPublished - 2015


  • Carboxypeptidase H/genetics
  • DNA Mutational Analysis
  • Diabetes Mellitus, Type 2/complications
  • Exome/genetics
  • Female
  • Gene Expression Regulation, Enzymologic
  • Homozygote
  • Humans
  • Intellectual Disability/complications
  • Klinefelter Syndrome/complications
  • Male
  • Mutation/genetics
  • Obesity, Morbid/complications
  • Pedigree
  • RNA, Messenger/genetics
  • Young Adult

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