ArticleProceedings of the National Academy of Sciences of the United States of America2003
Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 150 citations in OpenAlex.
- Cross-Species Sex Identification and Comparative Analysis of theAnimals : an open access journal from MDPI · 2026Article
- Let go or retain: role of calmodulin in orchestrating nuclear protein transport in eukaryotes.Plant cell reports · 2026Review
- Role of nucleobase-specific interactions in the binding and bending of DNA by human male sex determination factor SRY.The Journal of biological chemistry · 2024Article
- Disruption of theFrontiers in cell and developmental biology · 2023Article
- Early Gonadal Development and Sex Determination in Mammal.International journal of molecular sciences · 2022Review
- Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity.Frontiers in endocrinology · 2022Article
- Tenuous Transcriptional Threshold of Human Sex Determination. I. SRY and Swyer Syndrome at the Edge of Ambiguity.Frontiers in endocrinology · 2022Article
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- A novelClinical case reports · 2021Article
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- Structural basis for nuclear import selectivity of pioneer transcription factor SOX2.Nature communications · 2021Article
- A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of aProceedings of the National Academy of Sciences of the United States of America · 2019Article
- New Therapeutic Approach for Targeting Hippo Signalling Pathway.Scientific reports · 2019Article
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- Human Sex Determination at the Edge of Ambiguity: INHERITED XY SEX REVERSAL DUE TO ENHANCED UBIQUITINATION AND PROTEASOMAL DEGRADATION OF A MASTER TRANSCRIPTION FACTOR.The Journal of biological chemistry · 2016Article
- Article
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- The proinflammatory role of HECTD2 in innate immunity and experimental lung injury.Science translational medicine · 2015Article
- Article
- Regulation of male sex determination: genital ridge formation and Sry activation in mice.Cellular and molecular life sciences : CMLS · 2014Review
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Authors and funding
8 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
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 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 IMPbeta. The SRY-R133W mutant shows reduced IMPbeta 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 IMPbeta binding, whereas SRY-R75N and SRY-R76P show normal IMPbeta 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.
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