Commentary on: Peptidylglycine ?-amidating Monooxygenase is Required for Atrial Secretory Granule Formation

Bartels, Emil D.; Gøtze, Jens Peter; Mains, Richard E.; Eipper, Betty A.

doi:10.33696/cardiology.2.022

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…In the absence of PAM, proANP storage granules failed to form; the reintroduction of PAM facilitated proANP storage. Crucially, enzymatically inactive PAM also supported proANP storage ( 49 , 50 ), leading to the suggestion that PAM acts as a cargo receptor that directly binds to and protects newly synthesized proANP, facilitating its delivery to granules ( 9 , 49 ). A potential role for PAM as a cargo receptor in pituitary cells remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion

et al. 2023

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IntroductionPituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.MethodsFollowing the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.ResultsIn germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

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Section: Discussionmentioning

confidence: 99%

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion

et al. 2023

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“…Also, in murine atrial cells devoid of PAM that have depleted proANP storage, the reintroduction of PAM facilitated proANP storage. Crucially, this effect occurred irrespective of whether normal or enzymatically inactivated PAM was used [51, 52]. Interestingly, the depletion of proANP in the absence of PAM was unaccompanied by decreased proANP mRNA or protein biosynthesis, but rather occurred due to 3-fold increased basal ANP secretion.…”

Section: Discussionmentioning

confidence: 99%

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Trivellin

Daly

Hernández-Ramírez

et al. 2023

Preprint

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Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

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“…PAM is both a granin-like protein and a catalytic enzyme for amidation of peptides. Removal of PAM from cardiomyocytes results in the removal of granules, which underscores its key role in granular formation and biology [ 18 , 19 , 20 ]. For the enzymatic function of the protein; however, no amidated peptide has yet been identified in the granules (vide infra).…”

Section: Introductionmentioning

confidence: 99%

Biochemistry of the Endocrine Heart

Goetze

Bartels

Shalmi

et al. 2022

Biology

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Production and release of natriuretic peptides and other vasoactive peptides are tightly regulated in mammalian physiology and involved in cardiovascular homeostasis. As endocrine cells, the cardiac myocytes seem to possess almost all known chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. In several ways, intracellular granules in the cells contain not only peptides destined for secretion but also important granin molecules involved in maintaining a regulated secretory pathway. In this review, we will highlight the biochemical phenotype of the endocrine heart recapitulating that the cardiac myocytes are capable endocrine cells. Understanding the basal biochemistry of the endocrine heart in producing and secreting peptides to circulation could lead to new discoveries concerning known peptide products as well as hitherto unidentified cardiac peptide products. In perspective, studies on natriuretic peptides in the heart have shown that the post-translational phase of gene expression is not only relevant for human physiology but may prove implicated also in the development and, perhaps one day, cure of human cardiovascular disease.

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Commentary on: Peptidylglycine ?-amidating Monooxygenase is Required for Atrial Secretory Granule Formation

Cited by 3 publications

References 31 publications

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Biochemistry of the Endocrine Heart

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