Journal Article

New NR5A1 mutations and phenotypic variations of gonadal dysgenesis

Mönig, Isabel, Lünstedt, Ralf, Hiort, Olaf, Thorns, Christoph, Werner, Ralf, Wünsch, Lutz, Reiz, Benedikt, Krause, Alexandra, Binder, Gerhard, Schwab, Karl Otfried, Holterhus, Paul-Martin

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abnormalities / Adolescent / Adolescents / Adrenocorticotropic hormone / Age / Amenorrhea / Animal models / Binding / Biology and Life Sciences / Biosynthesis / Bladder / Case studies / Child / Childbirth & labor / Children / Chromosome abnormalities / Colliculus / Deoxyribonucleic acid / Development and progression / Diabetes mellitus / Diagnosis / Diamonds / Differentiation / Discrimination / Disorders / Division / DNA / Evaluation / Female / Females / Fertility / Follow-Up Studies / Frameshift mutation / Functional analysis / Gender / Gene deletion / Gene expression / Gene mutation / Genes / Genetic aspects / Genetic disorders / Genetic screening / Genetics / Genitalia / Genotype & phenotype / Gonadal disorders / Gonadal dysgenesis / Gonadal Dysgenesis - genetics / Gonadal Dysgenesis - physiopathology / Gonadal Dysgenesis - therapy / Gonads / Health aspects / HeLa Cells / Histology / Humans / Infants / Infertility / Laparoscopy / Male / Males / Mathematical models / Medicine / Medicine and Health Sciences / Mice / Missense mutation / Modulation / Mutation / Neonates / Nucleotide sequence / Ovaries / Phenotype / Phenotypes / Phenotypic variations / Pituitary (anterior) / Puberty / Reproductive system / Reproductive systems / Research and Analysis Methods / Sex determination / Spleen / Steroidogenic Factor 1 - genetics / Steroidogenic Factor 1 - metabolism / Surgery / T-Box Domain Proteins - genetics / Testosterone / Transcription / Tubes / Tumors / Urinary bladder / Urogenital system / Uterus / Vagina / Variability