The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development
Autor(a) principal: | |
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Data de Publicação: | 2011 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Brazilian Journal of Medical and Biological Research |
Texto Completo: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2011000400014 |
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. |
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The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex developmentGonadal dysgenesisHMG-boxMissense mutationSex reversal SRYStreak gonadsTestis determinationMale 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.Associação Brasileira de Divulgação Científica2011-04-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2011000400014Brazilian Journal of Medical and Biological Research v.44 n.4 2011reponame:Brazilian Journal of Medical and Biological Researchinstname:Associação Brasileira de Divulgação Científica (ABDC)instacron:ABDCinfo:eu-repo/semantics/openAccessCunha,J.L.Soardi,F.C.Bernardi,R.D.Oliveira,L.E.C.Benedetti,C.E.Guerra-Junior,G.Maciel-Guerra,A.T.de Mello,M.P.eng2011-11-11T00:00:00Zoai:scielo:S0100-879X2011000400014Revistahttps://www.bjournal.org/https://old.scielo.br/oai/scielo-oai.phpbjournal@terra.com.br||bjournal@terra.com.br1414-431X0100-879Xopendoar:2011-11-11T00:00Brazilian Journal of Medical and Biological Research - Associação Brasileira de Divulgação Científica (ABDC)false |
dc.title.none.fl_str_mv |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
title |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
spellingShingle |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development Cunha,J.L. Gonadal dysgenesis HMG-box Missense mutation Sex reversal SRY Streak gonads Testis determination |
title_short |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
title_full |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
title_fullStr |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
title_full_unstemmed |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
title_sort |
The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development |
author |
Cunha,J.L. |
author_facet |
Cunha,J.L. Soardi,F.C. Bernardi,R.D. Oliveira,L.E.C. Benedetti,C.E. Guerra-Junior,G. Maciel-Guerra,A.T. de Mello,M.P. |
author_role |
author |
author2 |
Soardi,F.C. Bernardi,R.D. Oliveira,L.E.C. Benedetti,C.E. Guerra-Junior,G. Maciel-Guerra,A.T. de Mello,M.P. |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Cunha,J.L. Soardi,F.C. Bernardi,R.D. Oliveira,L.E.C. Benedetti,C.E. Guerra-Junior,G. Maciel-Guerra,A.T. de Mello,M.P. |
dc.subject.por.fl_str_mv |
Gonadal dysgenesis HMG-box Missense mutation Sex reversal SRY Streak gonads Testis determination |
topic |
Gonadal dysgenesis HMG-box Missense mutation Sex reversal SRY Streak gonads Testis determination |
description |
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. |
publishDate |
2011 |
dc.date.none.fl_str_mv |
2011-04-01 |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2011000400014 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2011000400014 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
text/html |
dc.publisher.none.fl_str_mv |
Associação Brasileira de Divulgação Científica |
publisher.none.fl_str_mv |
Associação Brasileira de Divulgação Científica |
dc.source.none.fl_str_mv |
Brazilian Journal of Medical and Biological Research v.44 n.4 2011 reponame:Brazilian Journal of Medical and Biological Research instname:Associação Brasileira de Divulgação Científica (ABDC) instacron:ABDC |
instname_str |
Associação Brasileira de Divulgação Científica (ABDC) |
instacron_str |
ABDC |
institution |
ABDC |
reponame_str |
Brazilian Journal of Medical and Biological Research |
collection |
Brazilian Journal of Medical and Biological Research |
repository.name.fl_str_mv |
Brazilian Journal of Medical and Biological Research - Associação Brasileira de Divulgação Científica (ABDC) |
repository.mail.fl_str_mv |
bjournal@terra.com.br||bjournal@terra.com.br |
_version_ |
1754302939445329920 |