Type of mutations
• All the affected individuals described so far harboured homozygous loss-of-function (LoF) mutations in the CPE gene.
• No homozygosity for LoF variants in the general population database gnomAD (Genome Aggregation Database) has been listed.
• All mutations were identified through exome sequencing
• Identified mutations: 2 frameshift and 2 nonsense (NM_001873.3, NP_001864.1)
• c.[76_98del];[76_98del] p.[Glu26Argfs*68];[Glu26Argfs*68]
• c.[361C>T];[361C>T] p.[Arg121*];[Arg121*] (in two unrelated families)
• c.[405C>A]; c.[405C>A] p.[Tyr135*]; [(Tyr135*)]
• c.[994del];[994del] p.[Ser333Alafs*22];[Ser333Alafs*22]
Recommended genetic testing
• multi-gene panels which include CPE (for example analysis of developmental delay or obesity associated genes)
• exome sequencing (preferably trio)
Pathomechanism
• The CPE gene encodes the enzyme carboxypeptidase E, which is highly expressed in the endocrine and central nervous system. It has multiple functions including the generation of active neuropeptides and peptide hormones after cleavage of precursor proteins, direction of proneuropeptides and prohormones to their secretory pathways, regulation of vesicle transport in the neuronal cells and synapses, and neuroprotective function.
• Mouse models exhibit similar clinical manifestations with affected individuals. These were predominately attributed to impaired maturation of CPE target neuropeptides and peptide hormones.
CPE