A novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency

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dc.contributor.authorArtigas, Rocio A.
dc.contributor.authorGonzalez, Angel
dc.contributor.authorRiquelme, Erick
dc.contributor.authorCarvajal, Cristian A.
dc.contributor.authorCattani, Andreina
dc.contributor.authorMartinez Aguayo, Alejandro
dc.contributor.authorKalergis, Alexis M.
dc.contributor.authorPerez Acle, Tomas
dc.contributor.authorFardella, Carlos E.
dc.date.accessioned2024-01-10T13:45:54Z
dc.date.available2024-01-10T13:45:54Z
dc.date.issued2008
dc.description.abstractContext: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by unresponsiveness to ACTH. In this study, two mutations of the ACTH receptor (MC2R) gene are reported in this FGD clinical case.
dc.description.abstractObjective: The objective of the study was to characterize a novel MC2R gene mutation in a compound heterozygous patient with FGD phenotype.
dc.description.abstractDesign: This was a clinical case description, biochemical, molecular, and bioinformatics analysis to describe a novel MC2R gene mutation.
dc.description.abstractPatients: The subject of the study was a male diagnosed with primary adrenal insufficiency. The family history showed nonconsanguineous healthy parents, three healthy siblings, and one brother affected with FGD.
dc.description.abstractMain Outcome Measures: The mutant MC2R-Ala 126Ser showed significantly lower activity when it was stimulated with ACTH-(1-24) than did cells transfected with wild-type MC2R.
dc.description.abstractResults: The molecular studies demonstrated the presence of an adenine heterozygous insertion (InsA1347) in the MC2R gene (G217fs) in the patient. This insertion was due to a frame shift mutation in one allele and a premature stop codon codifying an aberrant receptor of 247 residues (27.2 kDa). We also found a novel heterozygous mutation alanine 126 by serine. Molecular dynamic simulations showed that serine 126 side chain fluctuates forming a noncanonical intrahelical hydrogen bond in the transmembrane helix 3 of the mutated receptor. This produces a structural rearrangement of the MC2R internal cavities that may affect the ligand recognition and signal transduction throughout the G protein.
dc.description.abstractConclusions: We propose a molecular explanation for the reduced activity exhibited by the MC2R alanine 126 by serine mutant.
dc.fechaingreso.objetodigital2024-05-15
dc.format.extent9 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1210/jc.2008-0048
dc.identifier.eissn1945-7197
dc.identifier.issn0021-972X
dc.identifier.pubmedidMEDLINE:18492762
dc.identifier.urihttps://doi.org/10.1210/jc.2008-0048
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/79095
dc.identifier.wosidWOS:000258240500024
dc.information.autorucMedicina;Artigas R;S/I;9174
dc.information.autorucMedicina;Carvajal C;S/I;8586
dc.information.autorucMedicina;Cattani A;S/I;99178
dc.information.autorucMedicina;Fardella C;S/I;66235
dc.information.autorucCiencias Biológicas;González A;S/I;1002683
dc.information.autorucCiencias Biológicas;Kalergis A;S/I;90610
dc.information.autorucMedicina;Martínez-Aguayo A;S/I;1003862
dc.information.autorucCiencias Biológicas;Pérez-Acle T;S/I;90704
dc.information.autorucMedicina;Riquelme E;S/I;1001194
dc.issue.numero8
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final3105
dc.pagina.inicio3097
dc.publisherENDOCRINE SOC
dc.revistaJOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
dc.rightsacceso restringido
dc.subjectPROTEIN-COUPLED RECEPTORS
dc.subjectACTH RESISTANCE SYNDROMES
dc.subjectADRENAL INSUFFICIENCY
dc.subjectCRYSTAL-STRUCTURE
dc.subjectTRANSMEMBRANE DOMAIN
dc.subjectGENE-MUTATIONS
dc.subjectDRY MOTIF
dc.subjectRHODOPSIN
dc.subjectACTIVATION
dc.subjectTEMPLATE
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleA novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency
dc.typeartículo
dc.volumen93
sipa.codpersvinculados9174
sipa.codpersvinculados8586
sipa.codpersvinculados99178
sipa.codpersvinculados66235
sipa.codpersvinculados1002683
sipa.codpersvinculados90610
sipa.codpersvinculados1003862
sipa.codpersvinculados90704
sipa.codpersvinculados1001194
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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