title: Novel polymorphisms and lack of mutations in the ACD gene in patients with ACTH resistance syndromes.
abstract: OBJECTIVE
  ACTH resistance is a feature of several human syndromes with known genetic causes, including familial glucocorticoid deficiency (types 1 and 2) and triple A syndrome. However, many patients with ACTH resistance lack an identifiable genetic aetiology. The human homolog of the Acd gene, mutated in a mouse model of adrenal insufficiency, was sequenced in 25 patients with a clinical diagnosis of familial glucocorticoid deficiency or triple A syndrome.
  
  
  METHODS
  A 3.4 kilobase genomic fragment containing the entire ACD gene was analysed for mutations in all 25 patients.
  
  
  METHODS
  Samples were obtained by three investigators from different institutions.
  
  
  METHODS
  The primary cohort consisted of 25 unrelated patients, primarily of European or Middle Eastern descent, with a clinical diagnosis of either familial glucocorticoid deficiency (FGD) or triple A syndrome. Patients lacked mutations in other genes known to cause ACTH resistance, including AAAS for patients diagnosed with triple A syndrome and MC2R and MRAP for patients diagnosed with familial glucocorticoid deficiency. Thirty-five additional patients with adrenal disease phenotypes were added to form an expanded cohort of 60 patients.
  
  
  METHODS
  Identification of DNA sequence changes in the ACD gene in the primary cohort and analysis of putative ACD haplotypes in the expanded cohort.
  
  
  RESULTS
  No disease-causing mutations were found, but several novel single nucleotide polymorphisms (SNPs) and two putative haplotypes were identified. The overall frequency of SNPs in ACD is low compared to other gene families.
  
  
  CONCLUSIONS
  No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease.
authors.affiliation: Department of Pediatrics, Division of Genetics, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA. keeganc@med.umich.edu
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Keegan
authors.forename: Janna E
authors.initials: JE
authors.lastname: Hutz
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Krause
authors.forename: Katrin
authors.initials: K
authors.lastname: Koehler
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Sotirios
authors.initials: S
authors.lastname: Stergiopoulos
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004931:Esophageal Achalasia / Q000235:genetics; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D000089804:Shelterin Complex; D013577:Syndrome; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: C495876:ACD protein, human; D005938:Glucocorticoids; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D000324:Adrenocorticotropic Hormone