Context Peptidylglycine-alpha-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 Malm & ouml; Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malm & ouml; 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 similar to 4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n similar to 4500 from MPP, and n similar to 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.
Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus
Giontella, Alice;Fava, Cristiano;
2024-01-01
Abstract
Context Peptidylglycine-alpha-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 Malm & ouml; Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malm & ouml; 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 similar to 4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n similar to 4500 from MPP, and n similar to 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.