title: 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.
authors.affiliation: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Suzanne I M
authors.initials: SI
authors.lastname: Alsters
authors.affiliation: Imperial Centre for Endocrinology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom; Centre for Neuropsychopharmacology and Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Goldstone
authors.affiliation: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom; Centre for Cardiovascular Genetics, UCL Institute of Cardiovascular Science, London, United Kingdom.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Buxton
authors.affiliation: NIHR Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Zekavati
authors.affiliation: NIHR Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Alona
authors.initials: A
authors.lastname: Sosinsky
authors.affiliation: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Andrianos M
authors.initials: AM
authors.lastname: Yiorkas
authors.affiliation: NW Thames Regional Genetics Service, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park Hospital, Harrow, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Holder
authors.affiliation: Department of Paediatrics, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Klaber
authors.affiliation: Department of Paediatric Endocrinology, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bridges
authors.affiliation: Department of Medical Genetics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.affiliation: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom; Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Carel W
authors.initials: CW
authors.lastname: le Roux
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Walley
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
authors.forename: Robin G
authors.initials: RG
authors.lastname: Walters
authors.affiliation: NIHR Imperial BRC Genomics Facility, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Section of Investigative Medicine, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
mesh_terms: D043423:Carboxypeptidase H / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics; D007713:Klinefelter Syndrome / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D009767:Obesity, Morbid / Q000150:complications* / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D043423:Carboxypeptidase H