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, sa.3, ss.163-169, 2013 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 80 Sayı: 3
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1159/000354086
  • Dergi Adı: HORMONE RESEARCH IN PAEDIATRICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.163-169
  • Anahtar Kelimeler: Adrenal insufficiency, Steroid synthesis, Sex reversal, Disorder of sex development, Lipoid congenital adrenal hyperplasia, STAR GENE, FEMALE-PATIENT, BINDING, CHOLESTEROL, MECHANISM, DOMAINS, COMPLEX, SITE
  • Çukurova Üniversitesi Adresli: Evet

Özet

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