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.

Abstract

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.

• Authors: Bilgin Yüksel, Alexandra E Kulle, Fatih Gürbüz, Maik Welzel, Damla Kotan, Eda Mengen, Paul-Martin Holterhus, Ali Kemal Topaloğlu, Joachim Grötzinger, Felix G Riepe
• Journal: Hormone research in paediatrics (Horm Res Paediatr) Vol. 80 Issue 3 Pg. 163-9 ( 2013) ISSN: 1663-2826 [Electronic] Switzerland
• PMID: 23920000 (Publication Type: Clinical Trial, Journal Article)
• Copyright: Copyright © 2013 S. Karger AG, Basel.

Chemical References

• Phosphoproteins
• steroidogenic acute regulatory protein
• Adrenodoxin
• Cholesterol
• Ferredoxin-NADP Reductase

Topics

• Adrenal Hyperplasia, Congenital (genetics, metabolism)
• Adrenal Insufficiency (congenital, genetics, metabolism)
• Adrenodoxin (genetics, metabolism)
• Amino Acid Substitution
• Animals
• COS Cells
• Child, Preschool
• Chlorocebus aethiops
• Cholesterol (genetics, metabolism)
• Disorder of Sex Development, 46,XY (genetics, metabolism)
• Ferredoxin-NADP Reductase (genetics, metabolism)
• Gonadal Dysgenesis, 46,XY (genetics, metabolism)
• Humans
• Infant
• Male
• Models, Molecular
• Mutation, Missense
• Phosphoproteins (chemistry, immunology, metabolism)
• Structure-Activity Relationship
• Turkey