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.
Highlights
An unknown proportion of severe cases of obesity are caused by monogenic disease
Absence of functional Carboxypeptidase E (CPE) in the fat/fat mouse and Cpe knockout mouse leads to abnormally low levels of a number of neuropeptides and peptide hormones resulting in a range of phenotypes, including late-onset obesity, hyperproinsulinaemia, infertility, anxiety and depression, hippocampal neuronal degeneration and memory deficits [4, 7,8,9,10,11]
In this study we present a novel form of monogenic obesity in humans by identifying for the first time a homozygous deleterious mutation in CPE, leading to complete lack of its expression
Summary
Many of the known monogenic forms of obesity, affecting appetite regulation through hypothalamic pathways, including the leptin-melanocortin pathway, were first identified from murine models of obesity. It is two decades since the discovery of defects in Lep and Lepr in the mouse models ob/ob and db/db respectively led to the discovery of the first monogenic obesity syndromes, leptin and leptin receptor deficiency, in humans [1, 2]. The more recently reported mutations in SH2B1 causing obesity and maladaptive behaviours followed on from investigation of the severely obese sh2b1-null mice models [3]. Another spontaneously occurring mutation causing murine obesity is the fat/fat mouse. Absence of functional CPE in the fat/fat mouse and Cpe knockout mouse leads to abnormally low levels of a number of neuropeptides and peptide hormones resulting in a range of phenotypes, including late-onset obesity, hyperproinsulinaemia, infertility, anxiety and depression, hippocampal neuronal degeneration and memory deficits [4, 7,8,9,10,11]
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