Evolutionary Landscape of SOX Genes to Inform Genotype-to-Phenotype Relationships

Abstract

The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype–phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG(High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood–brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box

Gene Therapy for Genetic Syndromes: Understanding the Current State to Guide Future Care

“…Thus, it has become common that gene therapies are initiated only in individuals that have either a variant that occurs in multiple individuals (often autosomal recessive conditions) or the variant results in a frameshift or nonsense change that removes large chunks of protein observed to be removed in other patients with the disorder. There is a need for characterizing VUSs rapidly using existing data [ 23 , 64 , 65 , 66 , 67 , 68 ], high-throughput wet lab techniques used in NAA10 characterizations [ 69 ], knowledge from paralog proteins such as the work on SOX transcription factors [ 70 ], or through crowd-sourcing variant lists to identify matching variant locations and phenotypes as was the case for MED13 [ 71 ].…”

Clinical Correlation of Transcription Factor SOX3 in Cancer: Unveiling Its Role in Tumorigenesis

“…These TFs influence cell differentiation, proliferation, migration, invasion, and metastasis in several tumor types [15][16][17][18][19][20]. The pleiotropic nature of SOX proteins is underscored by their ability to regulate different gene sets in diverse cellular contexts and tissues [9,21]. Adding to the complexity of cancer research is the variability observed in tumor types, genetic mutations, tumor locations, stages, patient characteristics, treatment responses, and drug resistance.…”

Clinical Correlation of Transcription Factor SOX3 in Cancer: Unveiling Its Role in Tumorigenesis

“…These TFs influence cell differentiation, proliferation, migration, invasion, and metastasis in several tumor types [ 16 , 17 , 18 , 19 , 20 , 21 ]. The pleiotropic nature of SOX proteins is underscored by their ability to regulate different gene sets in diverse cellular contexts and tissues [ 14 , 22 ]. The complexity of cancer research is compounded by the diversity observed across tumor types, genetic mutations, tumor sites, stages, patient characteristics, treatment responses and outcomes, further challenging the oncology field.…”