A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis.

Zeng, Yi‐Tao; Ren, Zhaorui; Zhang, Meilan; Huang, Ying; Zeng, Fanyi; Huang, Shu‐Zhen

doi:10.1136/jmg.30.8.655

Cited by 37 publications

(13 citation statements)

References 17 publications

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“…In the present study, we detected two missense mutations in two out of the three new patients: Arg132CGTAEGlyGGT was a novel mutation, while Ala113GCAAEThrACA was reported by Zeng et al (1993). We have previously reported finding SRY abnormalities in two out of three patients with the complete form of XY gonadal dysgenesis (Uehara et al 1999); thus, the final proportion of SRY aberrations was 67% (four of six patients).…”

Section: Discussionmentioning

confidence: 83%

Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation

et al. 2002

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Section: Discussionmentioning

confidence: 83%

Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation

et al. 2002

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“…2 Substitutions at the two positions in SOX9 studied here have also been reported at the corresponding positions in the HMG domain of SRY in two XY gonadal dysgenesis patients. The first example is SRY-A113T, analogous to SOX9-A158T, which showed reduced DNA binding like the SOX9-A158T mutant but also showed altered DNA bending (48). 3 This suggests that altering the secondary structure in this region of the HMG domain of SRY and SOX9 (which show 70% amino acid similarity) has different consequences.…”

Section: Discussionmentioning

confidence: 99%

Compound Effects of Point Mutations Causing Campomelic Dysplasia/Autosomal Sex Reversal upon SOX9 Structure, Nuclear Transport, DNA Binding, and Transcriptional Activation

Preiss¹,

Argentaro²,

Clayton³

et al. 2001

Journal of Biological Chemistry

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Human mutations in the transcription factor SOX9 cause campomelic dysplasia/autosomal sex reversal. Here we identify and characterize two novel heterozygous mutations, F154L and A158T, that substitute conserved "hydrophobic core" amino acids of the high mobility group domain at positions thought to stabilize SOX9 conformation. Circular dichroism studies indicated that both mutations disrupt ␣-helicity within their high mobility group domain, whereas tertiary structure is essentially maintained as judged by fluorescence spectroscopy. In cultured cells, strictly nuclear localization was observed for wild type SOX9 and the F154L mutant; however, the A158T mutant showed a 2-fold reduction in nuclear import efficiency. Importin-␤ was demonstrated to be the nuclear transport receptor recognized by SOX9, with both mutant proteins binding importin-␤ with wild type affinity. Whereas DNA bending was unaffected, DNA binding was drastically reduced in both mutants (to 5% of wild type activity in F154L, 17% in A158T). Despite this large effect, transcriptional activation in cultured cells was only reduced to 26% in F154L and 62% in A158T of wild type activity, suggesting that a small loss of SOX9 transactivation activity could be sufficient to disrupt proper regulation of target genes during bone and testis formation. Thus, clinically relevant mutations of SOX9 affect protein structure leading to compound effects of reduced nuclear import and reduced DNA binding, the net effect being loss of transcriptional activation. Campomelic dysplasia/autosomal sex reversal (CD/SRA1)1 is a severe skeletal malformation syndrome associated with XY male-to-female sex reversal caused by mutations in the SOX9 gene (1, 2). CD/SRA1 is an autosomal dominant disorder characterized by congenital bowing of the long bones and other skeletal malformations (narrow ilia, hypoplastic ischiopubic rami, micrognathia, cleft palate, and retroglossia), absence of olfactory bulbs and tracts, heart and renal malformations, hypoplastic lungs, narrow thoracic cage, defective tracheobronchial cartilages, small scapulae, and delayed bone age and psychomotor disorders (3, 4). In 75% of cases there is 46 XY testicular dysgenesis (5). The phenotypic changes seen in CD/ SRA1 patients correlate with sites of expression of SOX9 and suggest SOX9 is essential for the normal development of many organs. CD/SRA1 individuals are heterozygous resulting in haploinsufficiency of SOX9; presumably a critical dose of SOX9 is required to switch on appropriate genes during development. The present study reports the identification in two CD patients with novel amino acid substitution mutations, A154L and A158T in the HMG domain of SOX9, the latter in an XY female.To understand the functional consequences of these mutations, we attempted to correlate in vitro studies addressing protein structure, DNA binding, DNA bending, and importin recognition with in vivo studies of nuclear transport and transcriptional activation in cultured cells.

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“…The bipartite and basic cluster nuclear localization signals [33,34] are underlined. Mutation data are from literature current to December 1998 [8,9,38,69,71,[167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184].…”

Section: Transcriptional Activator or Repressor?mentioning

confidence: 99%

Sry and Sox9: mammalian testis-determining genes

Koopman¹

1999

CMLS, Cell. Mol. Life Sci.

141

100

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known to be downstream from Sry in this cascade is Abstract. Sry is the Y-chromosomal gene that acts as a trigger for male development in mammalian em-Sox9, which encodes a transcription factor related to Sry by the HMG box. Like Sry, mutations in Sox9 bryos. This gene encodes a high mobility group (HMG) box transcription factor that is known to disrupt male development, but unlike Sry, the role of Sox9 is not limited to mammals. This review focuses bind to specific target sequences in DNA and to cause a bend in the chromatin. DNA bending appears to be on what is known about the two genes and their likely modes of action, and draws together recent data part of the mechanism by which Sry influences transcription of genes downstream in a cascade of gene relating to how they might interconnect with the network of gene activity implicated in testis determinaregulation leading to maleness, but the direct targets of Sry remain to be positively identified. One gene tion in mammals.

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A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis.

Cited by 37 publications

References 17 publications

Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation

Complete XY gonadal dysgenesis and aspects of the SRY genotype and gonadal tumor formation

Compound Effects of Point Mutations Causing Campomelic Dysplasia/Autosomal Sex Reversal upon SOX9 Structure, Nuclear Transport, DNA Binding, and Transcriptional Activation

Sry and Sox9: mammalian testis-determining genes

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