ASCC1 is located on chromosome 10, at 10q22 and contains 13 exons (named 1–2, 3a, 3b, 4–8, 9a, 9b, 9c and 10) 11of which are coding and producing 20 different isoforms. ASCC1-related disease is due to biallelic variants of the gene, leading to an autosomal recessive phenotypes in patients. These include non-sense mutations (c.466C>T,p.Arg156Ter; c.667C>T,p.Glu223Ter; c.897G > A (p.Trp299*) in homozygous state; c.932C>G,p.Ser311Ter; c.1027C>T,p.Arg343Ter), hemizygous intragenic deletions (heterozygous deletion of exons 6-9a; heterozygous deletion of exon 5) and two frameshift variants: c.157dupG,p.Glu53GlyfsTer19 and c.464_465delTT,p.Phe155 SerfsTer15. The former represents the most recurrent variant, identified in several unrelated families, all originating from the Mediterranean area and this could reflect either the presence of a mutation hotspot or a common ancestor. Moreover, four splicing variants (c.297-8 T > G; c.626+1G>A; c.710+1G > A; c.871+1G > A;) are also published. All the reported variants, detected in homozygous state as well as in compound heterozygosity, are predicted to cause the complete absence of the protein, maybe due to the activation of the non-sense RNA decay. Indeed, this mechanism was demonstrated in cultured fibroblasts of affected subjects carrying the recurrent frameshift variant c.157dupG.
Finally, a distinct neuromuscular phenotype, characterized by neonatal hypotonia, delayed early motor and language development, in absence of dysphagia, dysphonia, respiratory dysfunction and congenital fractures, except the ulnar epiphysiolysis observed in neonatal period, was associated with two novel gene variants in compound heterozygosity: the splicing variant c.395-2A>G and the deletion of exons 1-2. Different clinical features and the milder phenotype presentation was ascribed to the overexpression of the truncated protein generated by the deleted allele, that retained a a full RNA ligase-like domain.
ASCC1 encodes a subunit of the tetrameric ASC-1 transcriptional cointegrator complex, composed also by TRIP4 (MIM: 604501), ASCC2 (MIM: 614216), and ASCC3 (MIM: 614217), all responsible of SMABF2 as well. This complex associates with transcription factors or with nuclear receptors and is likely involved in pre-mRNAs processing and regulation of splicing. Moreover, a key role in DNA repair has been postulated as well. Although the exact role of ASCC1 in the neuromuscular apparatus has not been well clarified so far, it is hypothed that is involved in several cell mechanisms and pathways, acting during the myogenesis by regulating both the cellular growth and differentiation.
ASCC1