Please use this identifier to cite or link to this item: http://archive.cmb.ac.lk:8080/xmlui/handle/70130/7076
Title: A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development
Authors: de Silva, K.S.H.
Bashamboo, Anu
Donohoue, Patricia A.
Vilain, Eric
Rojo, Sandra
Calvel, Pierre
Seneviratne, Sumudu N.
Buonocore, Federica
Barseghyan, Hayk
Bingham, Nathan
Rosenfeld, Jill A.
Mulukutla, Surya Narayan
Jain, Mahim
Burrage, Lindsay
Dhar, Shweta
Balasubramanyam, Ashok
Lee, Brendan
Members of UDN
Dumargne, Marie-Charlotte
Eozenou, Caroline
Suntharalingham, Jenifer P.
Lin, Lin
Bignon-Topalovic, Joelle
Poulat, Francis
Lagos, Carlos F.
McElreavey, Ken
Achermann, John C.
Keywords: phenotype
turner's syndrome
fibrinogen
karyotype determination procedure
mutation
adult
cell lineage
child
dna
genes
gonads
heterozygote
male infertility
mammals
menopause
premature
missense mutation
reproductive physiological process
relationship - sibling
genetics
ovary
testis
transcription factor
secondary physiologic amenorrhea
karyotype 46, xx
testicular dysgenesis
sexual development
wnt4 gene
Issue Date: 2016
Publisher: Oxford University Press
Citation: Bashamboo, A., Donohoue, P. A., Vilain, E., Rojo, S., Calvel, P., Seneviratne, S. N., ... & Achermann, J. C. (2016). A recurrent p. Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Human molecular genetics, 25(16), 3446-3453.
Abstract: Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY. Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.
URI: http://archive.cmb.ac.lk:8080/xmlui/handle/70130/7076
Appears in Collections:Department of Paediatrics

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A recurrent P. Arg92.pdfDisorders of (or differences in) sex development (DSD) are defined as congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical (1,2). Classic forms of DSD affect approximately one in every 2000 to 4000 people and may present in many ways, such as a baby with atypical genitalia where it cannot immediately be said whether the newborn is a boy or girl, or a teenage girl with primary amenorrhoea. Related conditions, such as hypospadias, are more prevalent, affecting up to one in 300 boys. DSDs encompass a wide range of different aetiologies (1–3). Sex chromosome mosaicism (45,X/46,XY) and 46,XY DSD (gonadal dysgenesis, disorders of androgen synthesis and action) are relatively common causes, whereas most individuals with 46,XX forms of DSD have congenital adrenal hyperplasia (CAH; MIM: 202010). Importantly, a subset of individuals with a 46,XX karyotype has ovotestes or testes rather than an adrenal condition. These forms of ovotesticular DSD (OTDSD) and testicular DSD (TDSD) were historically known as “true hermaphroditism” and “XX males”, respectively, and need different approaches to counselling and management compared to CAH (2,3). Our molecular understanding of the causes of OTDSD/TDSD is incomplete. Some individuals with OTDSD/TDSD have upregulation of genes involved in testis determination (e.g. SRY MIM: 400045, SOX9 MIM: 278850, SOX3 MIM: 300833), whereas others have reduced function of genes expressed in the developing ovary that repress testis development (e.g., RSPO1 MIM: 610644, WNT4 MIM: 611812; 4–9). To date, coding mutations in single genes causing non-syndromic OTDSD/TDSD have not been described. NR5A1, also known as steroidogenic factor-1 (SF-1) is a nuclear receptor transcription factor with key roles in reproductive development and function (10). Loss-of-function changes in NR5A1 are associated with a wide spectrum of conditions including gonadal (testicular) dysgenesis (MIM: 612965), hypospadias, and male factor infertility (MIM: 613957) in 46,XY individuals, as well as primary ovarian insufficiency (POI, MIM: 612964) in 46,XX women (11–15). Here, we show that a recurrent heterozygous point mutation in NR5A1 is associated with OTDSD/TDSD development in 46,XX individuals in four families of different ancestry.689.32 kBAdobe PDFView/Open


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