C12ORF57

C12orf57 encodes a highly conserved 126-amino-acid protein with no known paralogs that is ubiquitously expressed, including in the brain and eye, and is required for normal corpus callosum formation and ocular development (PMID:23453666, PMID:23453665). Homozygous or compound heterozygous loss-of-function mutations in C12orf57 cause an autosomal recessive syndrome characterized by corpus callosum hypoplasia or agenesis, colobomatous microphthalmia, intellectual disability, and intractable seizures (PMID:23453666, PMID:23453665, PMID:24798461). No enzymatic activity, binding partners, or molecular mechanism have been identified for the encoded protein.

1. 2013 Medium

   Two simultaneous studies established C12orf57 as a novel disease gene: homozygous and compound heterozygous loss-of-function mutations were shown to cause autosomal recessive corpus callosum abnormalities, colobomatous microphthalmia, seizures, and intellectual disability, revealing that this previously uncharacterized, highly conserved protein is essential for brain and eye development.

   Evidence Whole-exome sequencing and autozygome analysis in multiple consanguineous and non-consanguineous families, Sanger validation, mouse tissue expression profiling

   PMID:23453665 PMID:23453666

   Open questions at the time

   • No biochemical activity, subcellular localization, or binding partners identified
   • Animal models with targeted C12orf57 disruption have not been generated
   • Mechanism by which loss of C12orf57 leads to corpus callosum agenesis and coloboma is unknown
2. 2014 Medium

   Independent replication in a non-consanguineous family confirmed C12orf57 as the causative gene for this syndromic neurodevelopmental disorder, strengthening genotype–phenotype correlation but providing no new molecular insight.

   Evidence Exome sequencing and Sanger confirmation of compound heterozygous loss-of-function mutations with detailed clinical phenotyping

   PMID:24798461

   Open questions at the time

   • No functional assays or cellular studies performed
   • Protein structure and interaction network remain entirely unknown
   • Whether the protein acts cell-autonomously in neural or ocular progenitors is untested

• The molecular function of C12orf57 remains completely uncharacterized: no enzymatic activity, subcellular localization, signaling pathway involvement, or direct physical interactors have been experimentally determined.
• No biochemical or structural characterization of the protein
• No animal knockout or knockdown model with mechanistic analysis
• Downstream pathways disrupted by C12orf57 loss are unknown