Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract??? SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.
Adzhubei,
A method and server for predicting damaging missense mutations.
2010, Pubmed
Adzhubei,
A method and server for predicting damaging missense mutations.
2010,
Pubmed Arnold,
The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone.
2008,
Pubmed Bergsland,
The establishment of neuronal properties is controlled by Sox4 and Sox11.
2006,
Pubmed Bhattaram,
SOXC proteins amplify canonical WNT signaling to secure nonchondrocytic fates in skeletogenesis.
2014,
Pubmed Bhattaram,
Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors.
2010,
Pubmed Bienert,
The SWISS-MODEL Repository-new features and functionality.
2017,
Pubmed Chaoui,
Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome.
2011,
Pubmed Chen,
Orchestration of Neuronal Differentiation and Progenitor Pool Expansion in the Developing Cortex by SoxC Genes.
2015,
Pubmed Chen,
SOX4 is a potential prognostic factor in human cancers: a systematic review and meta-analysis.
2016,
Pubmed Cizelsky,
sox4 and sox11 function during Xenopus laevis eye development.
2013,
Pubmed
,
Xenbase Dy,
The three SoxC proteins--Sox4, Sox11 and Sox12--exhibit overlapping expression patterns and molecular properties.
2008,
Pubmed Gleeson,
Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein.
1998,
Pubmed Harley,
DNA binding activity of recombinant SRY from normal males and XY females.
1992,
Pubmed Hempel,
Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome.
2016,
Pubmed
,
Xenbase Hoffmeister,
Developmental neurogenesis in mouse and Xenopus is impaired in the absence of Nosip.
2017,
Pubmed
,
Xenbase Hoser,
Sox12 deletion in the mouse reveals nonreciprocal redundancy with the related Sox4 and Sox11 transcription factors.
2008,
Pubmed Hou,
Molecular basis for the genome engagement by Sox proteins.
2017,
Pubmed Jauch,
The crystal structure of the Sox4 HMG domain-DNA complex suggests a mechanism for positional interdependence in DNA recognition.
2012,
Pubmed Kamachi,
Sox proteins: regulators of cell fate specification and differentiation.
2013,
Pubmed Karaer,
A case of campomelic dysplasia in whom a new mutation was found in the SOX9 gene.
2014,
Pubmed Kato,
SOXC Transcription Factors Induce Cartilage Growth Plate Formation in Mouse Embryos by Promoting Noncanonical WNT Signaling.
2015,
Pubmed Katoh-Fukui,
Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9.
2015,
Pubmed Kozhemyakina,
A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation.
2015,
Pubmed Kwok,
Mutations in SOX9, the gene responsible for Campomelic dysplasia and autosomal sex reversal.
1995,
Pubmed Lamb,
Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features.
2012,
Pubmed Lefebvre,
Vertebrate skeletogenesis.
2010,
Pubmed Lefebvre,
SOXC Genes and the Control of Skeletogenesis.
2016,
Pubmed Lek,
Analysis of protein-coding genetic variation in 60,706 humans.
2016,
Pubmed Miller,
Transcriptional landscape of the prenatal human brain.
2014,
Pubmed Moody,
Segregation of fate during cleavage of frog (Xenopus laevis) blastomeres.
1990,
Pubmed
,
Xenbase Morín,
A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV.
2008,
Pubmed Mu,
SoxC transcription factors are required for neuronal differentiation in adult hippocampal neurogenesis.
2012,
Pubmed Nikolova,
Mechanisms of disease: Transcription factors in sex determination--relevance to human disorders of sex development.
2006,
Pubmed Okamoto,
Coffin-Siris syndrome and cardiac anomaly with a novel SOX11 mutation.
2018,
Pubmed Ortega,
The Subventricular Zone: A Key Player in Human Neocortical Development.
2018,
Pubmed Pingault,
Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.
2013,
Pubmed Pingault,
SOX10 mutations in patients with Waardenburg-Hirschsprung disease.
1998,
Pubmed Pontiggia,
Sex-reversing mutations affect the architecture of SRY-DNA complexes.
1994,
Pubmed Preiss,
Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation.
2001,
Pubmed Scharer,
Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells.
2009,
Pubmed Scherer,
Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations.
1998,
Pubmed Schilham,
Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4.
1996,
Pubmed Shim,
Cis-regulatory control of corticospinal system development and evolution.
2012,
Pubmed Sock,
Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.
2003,
Pubmed Sock,
Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling.
2004,
Pubmed Tsurusaki,
De novo SOX11 mutations cause Coffin-Siris syndrome.
2014,
Pubmed Turner,
Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns.
2015,
Pubmed Turner,
denovo-db: a compendium of human de novo variants.
2017,
Pubmed Urbán,
Neurogenesis in the embryonic and adult brain: same regulators, different roles.
2014,
Pubmed Venselaar,
Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces.
2010,
Pubmed Wang,
Identification of a novel mutation (Ala66Thr) of SRY gene causes XY pure gonadal dysgenesis by affecting DNA binding activity and nuclear import.
2018,
Pubmed Ware,
Interpreting de novo Variation in Human Disease Using denovolyzeR.
2015,
Pubmed Warman,
Nosology and classification of genetic skeletal disorders: 2010 revision.
2011,
Pubmed Wright,
Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.
2015,
Pubmed Yuan,
Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3.
1995,
Pubmed Zarrei,
A copy number variation map of the human genome.
2015,
Pubmed Zeng,
A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis.
1993,
Pubmed
