ArticleThe Journal of clinical endocrinology and metabolism2025
Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.
Article in The Journal of clinical endocrinology and metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Genetics of familial acromegaly and pituitary gigantism.The Journal of clinical endocrinology and metabolism · 2026Review
- Elucidating the susceptibility genes between insomnia and migraine by integrating genetic data and transcriptomes.The journal of headache and pain · 2026Article
- Shared genetic architecture between Parkinson's disease and self-reported sleep-related traits implicates theSleep advances : a journal of the Sleep Research Society · 2026Article
- A multi-omics Mendelian randomization study reveals PAM as a potential therapeutic target for type 2 diabetes.Journal of translational medicine · 2025Article
- Understanding peptide hormones: from precursor proteins to bioactive molecules.Trends in biochemical sciences · 2025Review
- Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.The Journal of clinical endocrinology and metabolism · 2025Article
- Enhancing Stability and Bioavailability of Peptidylglycine Alpha-Amidating Monooxygenase in Circulation for Clinical Use.Biomolecules · 2025Article
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12 authors.
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Abstract
contextPeptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides.
objectiveTo define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA).
designWe 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).
settingExome-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
participantsThis 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 measuresEndocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia.
resultsTwo 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.
conclusionPAM-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.
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