title: Compound heterozygosity of a frameshift mutation in the coding region and a single base substitution in the promoter of the ACTH receptor gene in a family with isolated glucocorticoid deficiency.
abstract: Isolated glucocorticoid deficiency (IGD) is an autosomal recessive syndrome characterized by glucocorticoid insufficiency without mineralocorticoid deficiency. Mutations in the coding region of the ACTH receptor (MC2R) have been reported in several families with IGD. We amplified and sequenced the entire MC2R coding region in a new family with IGD. The proband was found to be heterozygous (paternal allele) for the mutation Gly217fs, which changes the open reading frame of the MC2R protein resulting in a truncated receptor. No other abnormality was found in the MC2R coding region. However, sequencing of the promoter region of the MC2R gene (-1017/44 bp) of the proband revealed a heterozygous T-->C substitution in the maternal allele at -2 bp position from initiation of the transcription start site. This substitution was found in only 6.5% in a healthy unrelated population. Constructs containing this polymorphism consistently showed a significant 15% decrease in promoter activity compared to wild type. In conclusion, we provide evidence that the IGD in this previously unreported family with ACTH resistance appears to be secondary to compound heterozygosity of a coding region and a promoter mutation in the MC2R gene.
authors.affiliation: Hellenic National Diabetes Center, Athens, Greece. ctsigos@hndc.gr
authors.forename: Panayoula C
authors.initials: PC
authors.lastname: Tsiotra
authors.forename: Athina
authors.initials: A
authors.lastname: Koukourava
authors.forename: Valeria
authors.initials: V
authors.lastname: Kaltezioti
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Geffner
authors.forename: Danielle
authors.initials: D
authors.lastname: Naville
authors.forename: Martine
authors.initials: M
authors.lastname: Begeot
authors.forename: Sotirios A
authors.initials: SA
authors.lastname: Raptis
authors.forename: Constantine
authors.initials: C
authors.lastname: Tsigos
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D016368:Frameshift Mutation; D005938:Glucocorticoids / Q000172:deficiency*; D006579:Heterozygote; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D016366:Open Reading Frames; D018043:Receptors, Corticotropin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043202:Steroid Metabolism, Inborn Errors / Q000235:genetics*; D014162:Transfection
chemical_list: D017931:DNA Primers; D005938:Glucocorticoids; D018043:Receptors, Corticotropin; D004247:DNA