The SIAH1 gene encodes a RING-type E3 ubiquitin ligase belonging to the Seven in Absentia Homolog (SIAH) family. The enzyme carries out the ubiquitination of a wide variety of targets, either by direct binding or by acting as the essential RING domain subunit for larger E3 ubiquitin ligase complexes. By carrying out its function, the protein marks its targets for proteasomal degradation. Target substrates of SIAH1 include transcription regulators such as ELL2, MYB, POU2AF1, PML and RBBP8, the signal transduction molecules TIEG1 and NUMB, the cell surface receptor DCC and the anti-aopoptotic protein BAG1. It also ubiquitinates SYP, a protein involved in synaptic vesicle function in neurons. The protein is thus involved in the regulation of several key biological processes such as apoptosis, axon guidance, cell cycle, spermatogenesis and nervous system development.
The SIAH1 gene is located on the long arm of chromosome 16. It spans a length of 92 kb of DNA and its coding sequence is spread across 8 exons. The gene encodes a 31 kDa protein product comprised of 282 amino acids. Several isoforms of the SIAH1 protein exist due to alternatively spliced transcript variants. The gene is widely expressed in the human body, particularly in the nervous system, intestine, eye, pancreas, testis, ovary and placenta.
Monies et al. (2017) discussed the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, a 2-year-old male from a consanguineous family, presented with developmental delay and seizure disorder. Whole exome sequencing helped identify a homozygous mutation (c.91_91del, p.E31fs) in exon 1 of the patient’s SIAH1 gene. This gene mutation was considered a candidate for pathogenicity as it was a novel truncating variant; and the SIAH1 protein functions as an E3 ubiquitin ligase that binds to Piccolo and Bassoon, two presynaptic active zone proteins. Additional studies are required to independently confirm this association.
To contribute with your findings to the content of this record, please fill the CTGA Database Information Submission Form and email it, along with supportive documents, to firstname.lastname@example.org.