The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development
Braz. j. med. biol. res
; 44(4): 361-365, Apr. 2011. ilus
Article
en En
| LILACS
| ID: lil-581497
Biblioteca responsable:
BR1.1
ABSTRACT
Male sex determination in humans is controlled by the SRY gene, which encodes a transcriptional regulator containing a conserved high mobility group box domain (HMG-box) required for DNA binding. Mutations in the SRY HMG-box affect protein function, causing sex reversal phenotypes. In the present study, we describe a 19-year-old female presenting 46,XY karyotype with hypogonadism and primary amenorrhea that led to the diagnosis of 46,XY complete gonadal dysgenesis. The novel p.E89K missense mutation in the SRY HMG-box was identified as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. According to the three-dimensional structure of the human SRY HMG-box, the substitution of the conserved glutamic acid residue by the basic lysine at position 89 introduces an extra positive charge adjacent to and between the positively charged residues R86 and K92, important for stabilizing the HMG-box helix 2 with DNA. Thus, we propose that an electrostatic repulsion caused by the proximity of these positive charges could destabilize the tip of helix 2, abrogating DNA interaction.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
LILACS
Asunto principal:
Genes sry
/
Proteínas de Unión al ADN
/
Mutación
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Adolescent
/
Female
/
Humans
Idioma:
En
Revista:
Braz. j. med. biol. res
Asunto de la revista:
BIOLOGIA
/
MEDICINA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Brasil
Pais de publicación:
Brasil