CONTEXT: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. OBJECTIVE: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). DESIGN: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC
1991-1996
reexamination in 2002-2012), the Malmö Preventive Project (MPP
2002-2006), and the UK Biobank (UKB
2012). SETTING: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. PATIENTS OR OTHER PARTICIPANTS: This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB. MAIN OUTCOME MEASURES: Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. RESULTS: Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15
P = 2.5E-140] and 0.98 (1.04/0.92
P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31
95% CI: 1.16/1.47
P = 9.8E-06), independently of age and diabetes. CONCLUSION: PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.