Mutational screening of NR5A1 gene encoding steroidogenic factor 1 SF 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations

This study shows that NR5A1 mutations are a novel cause of severe primary spermatogenic impairment and suggests that isolated cryptorchidism might be another phenotype associated with disruption of NR5A1-mediated pathways.


Alberto Ferlin, Ph.D., Maria Santa Rocca, B.Sc., Cinzia Vinanzi, B.Sc., Marco Ghezzi, M.D., Andrea Di Nisio, Ph.D., Carlo Foresta, M.D.

Volume 104, Issue 1, Pages 163–169



To study the role of NR5A1 in cryptorchidism and male factor infertility. Mutations in NR5A1 have been initially associated with primary adrenal insufficiency and 46,XY gonadal dysgenesis and more recently with less severe phenotypes, including preliminary descriptions in severe forms of male factor infertility. Far less clear is the possible involvement of NR5A1 mutations in cryptorchidism.


Retrospective cross-sectional cohort study and functional analysis of mutant proteins.


University department.


Nine hundred fifty-nine subjects, including children with cryptorchidism and adults with different semen phenotypes associated or not associated with a history of cryptorchidism.



Main Outcome Measure(s):

Mutation screening of NR5A1 by sequencing all exons. Functional analysis of mutant proteins by transactivation assays of CYP11A1 and CYP17A1 promoters.


We identified seven undescribed and one previously described missense mutation in subjects with severe spermatogenic impairment, without (4/236, 1.7%) and with (3/85, 3.5%) a history of cryptorchidism. Newborns with cryptorchidism carry NR5A1 mutations at low frequency (0.7%), whereas no mutations were found in milder forms of infertility and normozoospermia, irrespective of the presence of cryptorchidism. The mutant proteins showed impaired transactivation of gonadal promoters. A single nucleotide polymorphism (rs1110061; c.437 G→C; p.Gly146Ala) was also associated with more severe forms of spermatogenic impairment with cryptorchidism.


This study, combined with what is already known about NR5A1-associated phenotypes, suggests considering mutations in this gene as a novel genetic cause of more severe forms of male factor infertility, especially when associated with a history of cryptorchidism.

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