Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias.
BACKGROUND
Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias.


RESULTS
We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein.


CONCLUSIONS
Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations.
Université Paris Descartes, Faculté de médecine and AP-HP, Hôpital Bicêtre, Unité d'Endocrinologie, Pédiatrique, Le Kremlin Bicêtre, France.
Slimane
S
Allali
Jean-Baptiste
JB
Muller
Raja
R
Brauner
Diana
D
Lourenço
Radia
R
Boudjenah
Vasiliki
V
Karageorgou
Christine
C
Trivin
Henri
H
Lottmann
Stephen
S
Lortat-Jacob
Claire
C
Nihoul-Fékété
Olivier
O
De Dreuzy
Ken
K
McElreavey
Anu
A
Bashamboo
D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000097:blood; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D058490:Disorder of Sex Development, 46,XY / Q000097:blood / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007021:Hypospadias / Q000097:blood / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007265:Inhibins / Q000097:blood; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D051381:Rats; D012189:Retrospective Studies; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
D054339:Steroidogenic Factor 1; C422364:inhibin B; D007265:Inhibins; D054304:Anti-Mullerian Hormone