Open AccessNew NR5A1 mutations and phenotypic variations of gonadal dysgenesis
Author(s) -
Ralf Werner,
Isabel Mönig,
Ralf Lünstedt,
Lutz Wünsch,
Christoph Thorns,
Benedikt Reiz,
Alexandra Krause,
Karl Otfried Schwab,
Gerhard Binder,
PaulMartin Holterhus,
Olaf Hiort
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0176720
Subject(s) - frameshift mutation , missense mutation , biology , genetics , gonadal dysgenesis , mutation , phenotype , micropenis , exome sequencing , germline mosaicism , gene , endocrinology , hypospadias
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. 18 DKVSG 22 del 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.