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.
Subject(s)
Adolescent , Female , Humans , Young Adult , DNA-Binding Proteins/genetics , Genes, sry/genetics , /genetics , Mutation/genetics , Follicle Stimulating Hormone/blood , /diagnosis , /surgery , KaryotypingABSTRACT
Quatorze pacientes de ambos os sexos, com idade variando de 27 a 76 anos, submetidos a cirurgias intra-oculares, receberam midazolam por via venosa, na dose de 0,07 mg.kg elevado a menos um, com o objetivo de se verificar sua açäo na pressäo intra-ocular (PIO). Nenhuma medicaçäo pré-anestésica foi administrada. A primeira medida foi efeuada assim que o paciente chegou ao centro cirúrgico; a segunda medida, cinco minutos após a administraçäo de midazolam. Houve queda da PIO, com significância estatística (p < 0,05). Portanto, para diminuir a PIO durante cirurgias intra-oculares, recomenda-se o midazolam por via venosa na dose de 0,07 mg.kg elevado a menos um