B670 - A combinatorial approach using steroidogenic factor 1 SF-1 NR5A1 to elucidate novel mechanisms in human biology - 16/06/2008

B number: 
Principal applicant name: 
Dr John Achermann (UCL Institute of Child Health, London, UK)
Prof Peter Hindmarsh (UCL Institute of Child Health, London, UK), Prof Steve Humphries (UCL Institute of Child Health, London, UK)
Title of project: 
A combinatorial approach using steroidogenic factor 1 (SF-1, NR5A1) to elucidate novel mechanisms in human biology
Proposal summary: 


Steroidogenic factor-1 (SF1, NR5A1) is a nuclear receptor that plays a central role in many aspects of adrenal, reproductive and metabolic function. Deletion of Sf1 (FtzF1) in mice causes adrenal and gonadal agenesis, and several loss of function mutations in SF1 have now been reported in humans with adrenal dysfunction and/or disorders of sex development. In addition to these well-established effects, Sf1 is also emerging as an important regulator of ventromedial hypothalamic development and programming, and post-natal obesity has been reported in Sf1 knock-out mice rescued by adrenal transplantation (1, 2). Although incidental reports of weight changes in patients with SF1 mutations exist, corticosteroid administration may have influenced growth in some cases, so the true role of SF1 in humans is still poorly understood.

Recent work has shown that a non-synonymous polymorphism exists in the coding sequence of SF1 (p.G146A, rs1110061) (3, 4). Studies in our laboratory have shown that this change does not affect nuclear localization or cellular dynamics, but does result in a mild but potentially significant effect on SF1 function in the transcriptional regulation of a range of target genes. In additional limited studies published recently, this polymorphim has been shown to be associated with undescended testes or micropenis in two small cohort studies in Japan (5, 6), and with an increased incidence of type 2 diabetes mellitus in the Chinese (7).

We have now undertaken analysis of this p.G146A polymorphism in SF1 in a UK-based cohort of mothers and children in the UCL Fetal Growth Study (Professor Peter Hindmarsh). This polymorphism is present in heterozygous state in approximately 8% of the 460 children studied and is in Hardy-Weinberg equilibrium. Heterozygosity for p.G146A was associated with a reduction in placental weight (643g vs 678g, pless than 0.05) and preterm delivery (15.3% vs 4.3%; Chi-square, 7.4; p=0.02; OR 0.25, 95% CI 0.09-0.77). Although there was no significant difference in birth weight between groups, analysis of post-natal growth data in a subset of children showed that a heterozygous p.G146A polymorphism was associated with higher BMI at three years of age (17.8 kg/m2 vs 16.3 kg/m2, pless than 0.001) and a significant elevation in both systolic and diastolic blood pressure.

We are therefore interested in establishing whether these findings can be reproduced in an independent population based cohort of children in the UK. It would also be of great interest to see if an association with undescended testes or hypospadias could be seen in the UK population, although it is possible that this would be underpowered and a case-control approach would be better.


We would aim to collaborate with K biosciences to establish the SF1 polymorphism (p.G146A, G/C, rs1110061) genotype status in the ALSPAC cohort. We would agree that genetyping the entire cohort would have potential added value in the long term, and would support this approach depending on cost implications. Taqman SNP genotyping probes for this change have been obtained from ABI and validated by Professor Steve Humphries at UCL for the study of an adult cohort, thus I would assume that K biosciences would be able proceed with this project without unexpected difficulties.

Date proposal received: 
Monday, 16 June, 2008
Date proposal approved: 
Monday, 16 June, 2008
Primary keyword: