title: The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia.
abstract: OBJECTIVE
  Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing's syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes.
  
  
  METHODS
  All of the nodules were obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocol and the ARMC5 sequence was determined by the Sanger method.
  
  
  RESULTS
  Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: six were frame shift, four were missense, three were nonsense, and one was a splice site variation. Allelic losses were confirmed in two of the nodules.
  
  
  CONCLUSIONS
  This is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, 'private,' and--in most cases--completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery.
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Correa
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Mihail
authors.initials: M
authors.lastname: Zilbermint
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Annabel
authors.initials: A
authors.lastname: Berthon
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Espiard
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Maria
authors.initials: M
authors.lastname: Batsis
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Georgios Z
authors.initials: GZ
authors.lastname: Papadakis
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Maya B
authors.initials: MB
authors.lastname: Lodish
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Jerome
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil fabio.faucz@nih.gov.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Faucz
authors.affiliation: Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, <ce:italic>Eunice Kennedy Shriver</ce:italic> National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000315:Adrenalectomy; D000328:Adult; D051186:Armadillo Domain Proteins; D003480:Cushing Syndrome / Q000235:genetics* / Q000601:surgery; D005260:Female; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D009154:Mutation; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000590373:ARMC5 protein, human; D051186:Armadillo Domain Proteins; D025521:Tumor Suppressor Proteins