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

Abstract

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.

Genetic obesity: next-generation sequencing results of 1230 patients with obesity

“…This could result in a higher diagnostic yield than the definite molecular diagnosis of 3.9% that we present here with NGS gene panel testing. Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel 26. These genes can be added to the next version of our diagnostic obesity gene panel.…”

A Novel Single Nucleotide T980C Polymorphism in the Human Carboxypeptidase E Gene Results in Loss of Neuroprotective Function

“…In fact, mutation in the CPE gene has been found in the brain from a patient with Alzheimer’ disease[10]. Furthermore, a person who bears homozygosity for a truncating mutation of the CPE gene displayed intellectual disability[19]. The hypothesis that CPE mutation would contribute to neurological disorders is also supported by the animal studies showing that CPE-KO mice had the neuronal loss of the CA3 region of hippocampus, displayed memory deficits and depressive-like behaviors[12,13,20].…”

“…Indeed, a recent study showed that a truncating mutation of the CPE gene found in a female from a consanguineous family, led to morbid obesity, intellectual disability, hypogonadotrophic hypogonadism and abnormal glucose homeostasis[19]. Additionally, a number of mutations in the human CPE gene have been reported and some are associated with endocrine problems.…”

“…In addition, CPE is relevant in AD as a study showed aberrant CPE accumulation in brains from patients with AD[17]. CPE knock-out mice and mice bearing a Ser202Pro mutation led to endocrine and neurological disorders including obesity, diabetes, neurodegeneration and infertility [7,10,18], while a human CPE truncating null mutation found in a patient, exhibited obesity, type 2 diabetes and intellectual disability [19]. The numerous functions of CPE, its association with disease and the detrimental effect of the lack of CPE in humans and mice due to gene mutations prompted us to search for human CPE mutations that may be relevant to human diseases.…”

Adiposopathy and epigenetics: an introduction to obesity as a transgenerational disease

“…In genomewide association studies (GWASs), the strongest genetic signal for body mass index is located in the FTO locus, wherein polymorphic differences in noncoding nucleotide sequences may change the basic function of human adipocytes from energy storage to energy utilization via enhanced thermogenesis 13,14 . Furthermore, monogenic diseases that cause severe cases of obesity are described and include leptin and leptin receptor deficiency, SH2B1 mutations, and carboxypeptidase E mutations [15][16][17] . Table 3 lists illustrative genetic obesity syndromes experienced by patients, and managed by clinicians, along with their genetic abnormalities [16][17][18][19][20][21][22][23][24] .…”