DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease

Abstract

DAX-1 (NR0B1) and SF-1 (NR5A1) are two nuclear receptor transcription factors that play a key role in human adrenal and reproductive development. Loss of DAX-1 function is classically associated with X-linked adrenal hypoplasia congenita. This condition typically affects boys and presents as primary adrenal insufficiency in early infancy or childhood, hypogonadotropic hypogonadism at puberty and impaired spermatogenesis. Late onset forms of this condition and variant phenotypes are increasingly recognized. In contrast, disruption of SF-1 only rarely causes adrenal insufficiency, usually in combination with testicular dysgenesis. Variants in SF-1/NR5A1 more commonly cause a spectrum of reproductive phenotypes ranging from 46,XY DSD (partial testicular dysgenesis or reduced androgen production) and hypospadias to male factor infertility or primary ovarian insufficiency. Making a specific diagnosis of DAX-1 or SF-1 associated conditions is important for long-term monitoring of endocrine and reproductive function, appropriate genetic counselling for family members, and for providing appropriate informed support for young people.

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

“…Currently , NR5A1 mutations represent one of the most frequent defects associated with 46,XY gonadal dysgenesis, accounting for up to 20% of cases (Suntharalingham et al, 2015). …”

“…(Suntharalingham et al, 2015) Sixteen different NR5A1 variants distributed across the full length of the protein have been described in patients with premature ovarian failure, and the majority of them are nonsynonymous mutations (Suntharalingham et al, 2015)…”

<b><i>NR0B1</i></b> Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

“…Our results indicate that hypomorphic NR0B1 mutations can be hidden in boys diagnosed with idiopathic PP. This phenotype may not be unique to the p.Glu3fsAla * 16, p.Gln37 * , and p.Trp39 * mutations, because some other substitutions in NR0B1 have also been associated with late-onset or latent adrenal insufficiency Suntharalingham et al, 2015].…”

“…Male patients carrying hemizygous NR0B1 mutations typically develop X-linked adrenal hypoplasia congenita (AHC), which is characterized by adrenal insufficiency during infancy or early childhood and hypogonadotropic hypogonadism and infertility at later ages [Suntharalingham et al, 2015]. Remarkably, patients with p.Gln37 * and p.Trp39 * mutations and certain other mutations exhibit late-onset or latent adrenal insufficiency with or without hypogonadism .…”

“…(alias DAX1 ), located at Xp21.2, encodes a transcription factor that plays pleiotropic roles in the development of the adrenal gland and the hypothalamicpituitary-gonadal (HPG) axis [Suntharalingham et al, 2015]. Male patients carrying hemizygous NR0B1 mutations typically develop X-linked adrenal hypoplasia congenita (AHC), which is characterized by adrenal insufficiency during infancy or early childhood and hypogonadotropic hypogonadism and infertility at later ages [Suntharalingham et al, 2015].…”