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Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations

Harding, Ruth E; Layfield, R; Mitchell, Claire; Forwood, Jade; John, Anna; Briggs, Lyndall; McDowall, Sharon; Jans, David A

Description

The architectural transcription factor SRY (sex-determining region of the Y chromosome) plays a key role in sex determination as indicated by the fact that mutations in SRY are responsible for XY gonadal dysgenesis in humans. Although many SRY mutations reduce DNA-binding/bending activity, it is not clear how SRY mutations that do not affect interaction with DNA contribute to disease. The SRY high-mobility group domain harbors two nuclear localization signals (NLSs), and here we examine SRY...[Show more]

dc.contributor.authorHarding, Ruth E
dc.contributor.authorLayfield, R
dc.contributor.authorMitchell, Claire
dc.contributor.authorForwood, Jade
dc.contributor.authorJohn, Anna
dc.contributor.authorBriggs, Lyndall
dc.contributor.authorMcDowall, Sharon
dc.contributor.authorJans, David A
dc.date.accessioned2015-12-13T22:31:41Z
dc.date.available2015-12-13T22:31:41Z
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/1885/75366
dc.description.abstractThe architectural transcription factor SRY (sex-determining region of the Y chromosome) plays a key role in sex determination as indicated by the fact that mutations in SRY are responsible for XY gonadal dysgenesis in humans. Although many SRY mutations reduce DNA-binding/bending activity, it is not clear how SRY mutations that do not affect interaction with DNA contribute to disease. The SRY high-mobility group domain harbors two nuclear localization signals (NLSs), and here we examine SRY from four XY females with missense mutations in these signals. In all cases, mutant SRY protein is partly localized to the cytoplasm, whereas wild-type SRY is strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins (IMPs) and requires unidentified cytoplasmic transport factors, whereas the C-terminal NLS is recognized by IMPβ. The SRY-R133W mutant shows reduced IMPβ binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the N-terminal NLS mutants examined, SRY-R62G unexpectedly shows a marked reduction in IMPβ binding, whereas SRY-R75N and SRY-R76P show normal IMPβ binding, suggesting defects in the IMP-independent pathway. We conclude that SRY normally requires the two distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. This study documents cases of human disease being explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus.
dc.publisherNational Academy of Sciences (USA)
dc.sourcePNAS - Proceedings of the National Academy of Sciences of the United States of America
dc.subjectKeywords: carrier protein; karyopherin beta; testis determining factor; transcription factor; unclassified drug; amino acid substitution; animal cell; article; carboxy terminal sequence; case report; DNA binding; DNA integration; gene mutation; gonadal dysgenesis;
dc.titleDefective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume100
dc.date.issued2003
local.identifier.absfor060499 - Genetics not elsewhere classified
local.identifier.ariespublicationMigratedxPub4589
local.type.statusPublished Version
local.contributor.affiliationHarding, Ruth E, King's College London
local.contributor.affiliationLayfield, R, University of Nottingham
local.contributor.affiliationMitchell, Claire, Cytopia Pty Ltd
local.contributor.affiliationForwood, Jade, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationJohn, Anna, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBriggs, Lyndall, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationMcDowall, Sharon, Howard Florey Institute
local.contributor.affiliationJans, David A, College of Medicine, Biology and Environment, ANU
local.bibliographicCitation.issue12
local.bibliographicCitation.startpage7045
local.bibliographicCitation.lastpage7050
local.identifier.doi10.1073/pnas.1137864100
dc.date.updated2015-12-11T09:02:07Z
local.identifier.scopusID2-s2.0-0038810142
CollectionsANU Research Publications

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