The Novel Mutation p.Trp147Arg of the Steroidogenic Acute Regulatory Protein Causes Classic Lipoid Congenital Adrenal Hyperplasia with Adrenal Insufficiency and 46,XY Disorder of Sex Development

YÜKSEL B. , Kulle A. E. , GÜRBÜZ F. , Welzel M., Kotan D. , Mengen E., ...Daha Fazla

HORMONE RESEARCH IN PAEDIATRICS, cilt.80, ss.163-169, 2013 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 80 Konu: 3
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1159/000354086
  • Sayfa Sayıları: ss.163-169


Background: The steroidogenic acute regulatory protein (StAR) is essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause lipoid congenital adrenal hyperplasia. Objective and Methods: To identify causative mutations in a patient presenting with adrenal failure during early infancy. The objective was to study the functional and structural consequences of the novel StAR mutation p.Trp147Arg in a Turkish patient detected in compound heterozygosity with the p.Glu169Lys mutation. Results: Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.Trp147Arg mutant. The previously described p.Glu169Lys mutant led to significantly lower cholesterol conversion than wild-type StAR protein. As derived from three-dimensional protein modeling, the residue W147 is stabilizing the C-terminal helix in a closed conformation hereby acting as gatekeeper of the ligand cavity of StAR. Conclusions: The novel mutation p.Trp147Arg causes primary adrenal insufficiency and complete sex reversal in the 46,XY patient. Clinical disease, in vitro studies and three-dimensional protein modeling of the mutation p.Trp147Arg underscore the relevance of this highly conserved residue for StAR protein function. Copyright (c) 2013 S. Karger AG, Basel