SIX3

Highest pathogenic variant AF is 0.0000055398823

Gene type

protein_coding

Transcript type

protein_coding

Transcript

ENST00000260653

Coding exons

2

Length

4315

Individuals with no LoFs

117557

Homozygous LoFs

0

Heterozygous LoFs

2

Defined

117559

p

0.00000851

Function

FUNCTION: Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 AND CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is AES and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 functions also in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway (By similarity). Plays a role in eye development by suppressing WNT1 expression and in dorsal- ventral patterning by repressing BMP signaling pathway. {ECO:0000250|UniProtKB:Q62233, ECO:0000269|PubMed:18791198}.;

Disease

DISEASE: Holoprosencephaly 2 (HPE2) [MIM:157170]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. {ECO:0000269|PubMed:10369266, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15523651, ECO:0000269|PubMed:17001667, ECO:0000269|PubMed:18791198, ECO:0000269|PubMed:20531442}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Schizencephaly (SCHZC) [MIM:269160]: Extremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. Large portions of the cerebral hemispheres may be absent and replaced by cerebro- spinal fluid. {ECO:0000269|PubMed:20157829}. Note=The disease is caused by mutations affecting the gene represented in this entry.;