TY - JOUR
T1 - New NR5A1 mutations and phenotypic variations of gonadal dysgenesis
AU - Werner, Ralf
AU - Mönig, Isabel
AU - Lünstedt, Ralf
AU - Wünsch, Lutz
AU - Thorns, Christoph
AU - Reiz, Benedikt
AU - Krause, Alexandra
AU - Schwab, Karl Otfried
AU - Binder, Gerhard
AU - Holterhus, Paul Martin
AU - Hiort, Olaf
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Mutations in NR5A1 have been reported as a frequent cause of 46, XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46, XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs∗83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling's family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.
AB - Mutations in NR5A1 have been reported as a frequent cause of 46, XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46, XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs∗83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling's family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.
UR - http://www.scopus.com/inward/record.url?scp=85018989848&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0176720
DO - 10.1371/journal.pone.0176720
M3 - Journal articles
C2 - 28459839
AN - SCOPUS:85018989848
SN - 1553-7390
VL - 12
JO - PLoS ONE
JF - PLoS ONE
IS - 5
M1 - e0176720
ER -