The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

Autor(es)

Cunha, J. L. ^[1] ; Soardi, F. C. ^[1] ; Bernardi, R. D. ^[1] ; Oliveira, L. E. C. ^[1] ; Benedetti, C. E. ^[2] ; Guerra-Junior, G. ^{[3, 4]} ; Maciel-Guerra, A. T. ^{[5, 4]} ; de Mello, M. P. ^{[1, 4]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Campinas, SP - Brazil

^[2] Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Fac Ciencias Med, Grp Interdisciplinar Estudos Determinacao & Difer, Campinas, SP - Brazil

^[5] Univ Estadual Campinas, Fac Ciencias Med, Dept Med Genet, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Brazilian Journal of Medical and Biological Research; v. 44, n. 4, p. 361-365, APR 2011.
• Citações Web of Science: 6

Resumo

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. (AU)

• Processo FAPESP: 02/13237-4 - Analise da regulacao da expressao do gene sry pela proteina sp1.
• Beneficiário: Luiz Eduardo Chimello de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 08/54776-1 - Disgenesia gonodal xy: identificacao de mutacoes nas regioes codificadora e promotora do gene sry e analise de seus efeitos na estrutura proteica e na expressao genica
• Beneficiário: Maricilda Palandi de Mello
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/03168-1 - Análise da regulação da expressão do gene SRY pelas proteínas SP1 e WT1
• Beneficiário: Fernanda Caroline Soardi
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/00900-0 - Análises de mutações e de seus efeitos na expressão do gene SRY em casos de Disgenesia Gonadal XY
• Beneficiário: José Luiz Rosenberis Cunha Júnior
• Modalidade de apoio: Bolsas no Brasil - Mestrado