Mutation screening and tissue expression patterns implicate SRY-box 14 (SOX14) in human eye and brain developmental anomalies

Abstract

Anophthalmia, microphthalmia and coloboma (AMC) are developmental eye anomalies which occur in approximately 3 in 10,000 births. They are a genetically heterogeneous group of conditions, with over 300 genes having been identified as underlying them. However, only approximately 25% of patients receive a genetic diagnosis, depending on phenotype. The most frequent genetic cause of severe AMC are alterations in SOX2, a member of the SOXB family of transcription factors which have important functions in early central nervous system development. Both SOX2 and SOX14 bind the same transcription factor binding site, acting as enhancers and repressors, respectively. Therefore, SOX14 may mediate SOX2 targeted gene transcription and so be a candidate for AMC. We screened SOX14 in 306 individuals with developmental eye anomalies and identified four families carrying variants: a de novo heterozygous c.242G>T (p.Arg81Leu), a maternally inherited frameshift c.722delA, a de novo deletion of 7.78Mb including SOX14, and a paternally inherited SOX14 duplication. However, the link between the identified variations and the ocular phenotype still remain to be demonstrated. Furthermore, in situ hybridisation experiments using human embryonic tissue demonstrated that SOX14 is expressed in the eye and regions of the brain, including the hindbrain and diencephalon. Although, we developed a zebrafish model carrying CRISPR-induced mutations of sox14, these fish showed no alterations in eye development or gross anatomical abnormalities. We consider SOX14 to be a likely important candidate in mammalian nervous system development and should be considered a candidate for AMC disorders

Anophthalmia, microphthalmia and coloboma (AMC) are developmental eye anomalies which occur in approximately 3 in 10,000 births. They are a genetically heterogeneous group of conditions, with over 300 genes having been identified as underlying them. However, only approximately 25% of patients receive a genetic diagnosis, depending on phenotype. The most frequent genetic cause of severe AMC are alterations in SOX2, a member of the SOXB family of transcription factors which have important functions in early central nervous system development. Both SOX2 and SOX14 bind the same transcription factor binding site, acting as enhancers and repressors, respectively. Therefore, SOX14 may mediate SOX2 targeted gene transcription and so be a candidate for AMC. We screened SOX14 in 306 individuals with developmental eye anomalies and identified four families carrying variants: a de novo heterozygous c.242G>T (p.Arg81Leu), a maternally inherited frameshift c.722delA, a de novo deletion of 7.78Mb including SOX14, and a paternally inherited SOX14 duplication. However, the link between the identified variations and the ocular phenotype still remain to be demonstrated. Furthermore, in situ hybridisation experiments using human embryonic tissue demonstrated that SOX14 is expressed in the eye and regions of the brain, including the hindbrain and diencephalon. Although, we developed a zebrafish model carrying CRISPR-induced mutations of sox14, these fish showed no alterations in eye development or gross anatomical abnormalities. We consider SOX14 to be a likely important candidate in mammalian nervous system development and should be considered a candidate for AMC disorders