Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.
BACKGROUND
Very few patients have been described with isolated 17,20-lyase deficiency who have had their mutations in P450c17 (17alpha-hydroxylase/17,20-lyase) proven by DNA sequencing and in vitro characterization of the mutations. Most patients with 17,20-lyase deficiency have mutations in the domain of P450c17 that interact with the electron-donating redox partner, P450 oxidoreductase (POR).


OBJECTIVE
Our objective was to clarify the genetic and functional basis of isolated 17,20-lyase deficiency in familial cases who were previously reported as having 17,20-lyase deficiency.


METHODS
Four undervirilized males of an extended Bedouin family were investigated. One of these has previously been reported to carry mutations in the CYP17A1 gene encoding P450c17 causing isolated 17,20-lyase deficiency.


METHODS
Serum hormones were evaluated before and after stimulation with ACTH. Urinary steroid metabolites were profiled by gas chromatography-mass spectrometry. Exons 1 and 8 of CYP17A1 previously reported to harbor mutations in one of these patients and all 15 coding exons of POR were sequenced.


RESULTS
Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in two different laboratories showed no mutations. Sequencing of POR showed that all four patients were homozygous for G539R, a previously studied mutation that retains 46% of normal capacity to support the 17alpha-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17.


CONCLUSIONS
POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency.
Hershkovitz
Eli
E
Pediatric Endocrinology and Metabolic Unit, Soroka University Medical Center, P.O. Box 151, Beer Sheva 84101, Israel. elih@bgu.ac.il
Parvari
Ruthi
R
Wudy
Stefan A
SA
Hartmann
Michaela F
MF
Gomes
Larissa G
LG
Loewental
Neta
N
Miller
Walter L
WL
D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis* / Q000235:genetics*; D000328:Adult; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D003241:Consanguinity; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005190:Family; D005998:Glycine / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
D001120:Arginine; D013254:Steroid 17-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; D005998:Glycine