Role of the spliceosome-associated gene, SON in regulating RNA splicing through intron retention and exon skipping to maintain the pluripotency of human embryonic stem cells (hESCs) and cell-cycle progression. Role of SON in RNA Splicing The SON gene encodes the SON protein, which is able to bind to DNA and RNA. The SON protein is mainly localised to nuclear speckles and involved in a variety of cellular processes such as transcription, cell cycle regulation and subnuclear organisation of pre-messenger RNA (mRNA) splicing. SON contains various domains such as the RS-rich domain, a G-patch domain and a double-stranded RNA-binding motif. The presence of these domains is necessary for SON to mediate constitutive and alternative splicing. The RS-rich domain serves to localise SON in nuclear speckles with pre-mRNA processing factors. The functional domains and specific localisation of SON in nuclear speckles has indicated its role in pre-mRNA splicing. SON also plays a key role in alternative splicing of exons. SON is required for genome stability by ensuring the efficiency of RNA splicing of weak constitutive and alternative splice sites. SON-dependent cell-cycle genes possess a weak 5’ or 3’ splice site and are dependent on SON to ensure efficient splicing and spliceosome recognition. Role of SON in Embryonic Development The SON gene also plays a critical role during development. SON is expressed preferentially in undifferentiated stem cells. Depletion of SON results in stem cell differentiation. Human embryonic stem cells (hESCs) are able to undergo lineage-specific differentiation into specific types of cells, known as pluripotency. Pluripotent stem cells, such as hESCs can undergo gastrulation to give rise to the three germ layers. A significant level of SON expression in fetal tissue has suggested a regulatory role of SON in cellular proliferation and or differentiation during embryonic development by influencing the splicing of pluripotency maintenance genes. The expression of transcription factors such as the SON factor and epigenetic modifiers regulate the pluripotency of hESCs by ensuring genes undergo RNA splicing to create a mature RNA transcript. The SON gene is required for RNA splicing of transcripts encoding the cell-cycle protein TUBG1 and genes maintaining hESC pluripotency; PRDM14, OCTA, E4F1 and MED24 in hESCs. As OCT4 is involved in the core transcriptional circuitry in hESCs, misregulation of OCT4 induces cell differentiation. PRDM14 is a pluripotency regulator and MED24 is a mediator complex essential in the maintenance of pluripotency. In wild-type ESCs, SON binding to the RNA transcripts of pluripotency regulating genes such as PRDM14 and OCT4 results in correct splicing and maintenance of pluripotency. Effects of SON Haploinsufficiency on RNA Splicing and Embryonic Development The downregulation of SON can impact the regulation of mitotic regulator transcripts and cause defects in cell survival and the developmental process. SON depletion causes decreased cell growth, disarrayed microtubule processes and disordered spindle pole separation, causing mitotic arrest at metaphase and severe genome integrity impairment. Mitotic cells without functional SON have increased double-stranded DNA breaks and micronuclei formation. Consequently, genome stability and regulation of the cell cycle are compromised, contributing to the development of multi-organ defects in<unk>  patients. Aberrant splicing and de novo heterozygous LoF mutations in SON gene disrupts the process of gene expression and can result in SON haploinsufficiency.<unk>  individuals with SON haploinsufficiency display decreased mRNA expression and abnormal RNA splicing products of numerous genes which are necessary for neuronal cell migration, metabolic processes and neurodevelopment of the brain. RNA analyses from affected individuals with<unk>  confirmed the downregulation of genes essential for neuronal migration and cortex organisation (TUBG1, FLNA, PNKP, WDR62, PSMD3, HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA). Aberrant SON-mediated RNA splicing results from the accumulation of mis-spliced transcripts. The mis-spliced RNA products are caused by significant intron retention (TUBG1, FLNA, PNKP, WDR62, PSMD3, PCK2, PFKL, IDH2, and ACY1) and exon skipping (HDAC6 and ADA). In contrast, the parents of individuals with<unk>  display an absence of mis-spliced RNA products. SON depletion downregulates and causes aberrant splicing of the pluripotency factors, OCT4, PRDM14, MED24 and E4F1, inducing spontaneous differentiation of hESCs followed by widespread cell death. As SON acts as an intron splicing activator, the depletion of SON leads to increased intron retention and exon skipping in hESCs in regulatory genes of the cell cycle and hESC identity. Mutations in the SON gene and or SON haploinsufficiency compromises SON-mediated RNA splicing and contributes to the complex developmental defects observed in individuals with<unk> . Erroneous SON function causes insufficient production of downstream targets, genome instability and disrupted cell cycle progression which are fundamental to the developmental defects and organ abnormalities in individuals with<unk> . For example, FLNA haploinsufficiency observed in individuals with<unk>  is the main cause of a rare brain disorder, periventricular nodular heterotopia. De novo LoF mutations in TUBG1 can result in microcephaly and cortical malformations due to compromised SON-mediated RNA splicing in affected<unk>  individuals. The consequence of SON haploinsufficiency on embryonic development has also been studied in zebrafish animal models (Danio rerio). A range of developmental defects was observed, including bent, shortened or gnarled tails, massive body curvatures with deformed body axes, eye malformations and microcephaly. Embryos that survived for a longer period of time have more severe phenotypes such as spinal malformations with brain oedema, imitating features observed in affected<unk>  individuals.
ZTTK syndrome
ATR-16 syndrome
CAMFAK syndrome
ATR-X syndrome
Treacher Collins syndrome
MEDNIK syndrome
GRACILE syndrome
LIG4 syndrome