Overview of repeats
Polyalanine expansions in the exon 3 of the RUNX2 gene (also known as CBFA1) have been associated with the cleidocranial dysplasia (CCD). In one study conducted by Mundlos et al. (1997) discovered a family where six members carried an expanded allele. The repeat size in these patients was 27, whereas the normal length is 17 alanine repeats (Mundlos et al., 1997).
In 2015, a case study was published reporting on a Japanese patient with CCD who harbored a rare variant of the RUNX2 gene, resulting in an expansion of three alanine residues in the polyalanine tract (c.181_189dupGCGGCGGCT). Subsequent in vitro experiments revealed that the expanded RUNX2 formed intracellular ubiquitinated aggregates and exerted a dominant negative effect. In comparison to a RUNX2 variant with a 10 alanine expansion, it exhibited slower aggregation growth. These findings suggest that the presence of the RUNX2 (+3 Ala) variant was associated with CCD in this particular case, and the accumulation of intracellular aggregates correlated with the length of the alanine tract (Shibata et al., 2016).