title: Neonatal presentation of familial glucocorticoid deficiency resulting from a novel splice mutation in the melanocortin 2 receptor accessory protein.
abstract: BACKGROUND
  Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Mutations in the ACTH receptor/melanocortin 2 receptor (MC2R), the MC2R accessory protein (MRAP) or the STAR protein (STAR) cause FGD types 1, 2 and 3, respectively, accounting for ~50% of all cases.
  
  
  METHODS
  We report a neonate of Indian origin, who was diagnosed with FGD in the first few days of life. He presented with hypoglycaemic seizures and was noted to have generalised intense hyperpigmentation and normal male genitalia. Biochemical investigations revealed hypocortisolaemia (cortisol 0.223 μg/dl; NR 1-23 μg/dl) and elevated plasma ACTH (170 pg/ml). Serum electrolytes, aldosterone and plasma renin activity were normal. Peak cortisol following a standard synacthen test was 0.018 μg/dl. He responded to hydrocortisone treatment and continues on replacement. Patient DNA was analysed by direct sequencing. The effect of the novel mutation was assessed by an in vitro splicing assay using wild type and mutant heterologous minigenes.
  
  
  RESULTS
  A novel homozygous mutation c.106+2_3dupTA was found in the MRAP gene. Both parents were heterozygous for the mutation. In an in vitro splicing assay, the mutation resulted in the skipping of exon 3.
  
  
  CONCLUSIONS
  We have identified a novel MRAP mutation where disruption of the intron 3 splice-site results in a prematurely terminated translation product. This protein (if produced) would lack the transmembrane domain that is essential for MC2R interaction. We predict that this would cause complete lack of ACTH response thus explaining the early presentation in this case.
authors.affiliation: Division of Paediatric Endocrinology, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: V
authors.initials: V
authors.lastname: Jain
authors.forename: L A
authors.initials: LA
authors.lastname: Metherell
authors.forename: A
authors.initials: A
authors.lastname: David
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: P K
authors.initials: PK
authors.lastname: Sharma
authors.forename: A J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: L F
authors.initials: LF
authors.lastname: Chan
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000235:genetics; D000367:Age Factors; D005938:Glucocorticoids / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D005938:Glucocorticoids; C458099:MRAP protein, human; D008565:Membrane Proteins; D022821:RNA Splice Sites; D000324:Adrenocorticotropic Hormone