Novel RUNX2 frameshift mutations in Chinese patients with cleidocranial dysplasia

Abstract

Cleidocranial dysplasia (CCD) is a skeletal disorder caused by heterozygous mutations in the runt-related transcription factor 2 (RUNX2) gene. We evaluated the phenotypes of eight Chinese patients with CCD from three unrelated families followed by analysis of the RUNX2 genes. Three different RUNX2 frameshift mutations were identified. Two of the mutations are novel (c.887insC and c.592delA) and one (c.90insC) has been described previously. Surprisingly, the patient with the most severely truncated RUNX2 protein (c.90insC) had the mildest phenotype. The RUNX2 mutations identified were assessed for their effect on the subcellular localization of the mutant RUNX2 proteins because of previously reported inconsistent findings. All three mutant proteins showed at least partially impaired nuclear localization compared with wild-type RUNX2, which was localized exclusively in the nucleus. Our findings support the notion that haploinsufficiency of RUNX2 may be mainly responsible for CCD. However, because the correlation between the severity of the phenotype and the degree of mutational impairment of RUNX2 is not consistent, other factors, such as nonsense-mediated mRNA decay and negative dominant effects, may also play a role. In addition, we show that despite the presence of the best characterized nuclear localization signal, nuclear translocation of truncated RUNX2 can be inhibited, possibly as a result of precipitation in the cytoplasm.

Cleidocranial dysplasia and RUNX2‐clinical phenotype–genotype correlation

“…Majority of RUNX2 mutations in individuals suffering from classic CCD occur in the runt domain and the most common DNA disruptions are missense mutations that prevent RUNX2 binding to DNA or nonsense mutations that result in biosynthesis of truncated protein. While missense mutations are uniquely found within runt‐domain region, nonsense and frame‐shift types were described throughout the gene (Fig. , Table ).…”

Functional analysis of novel RUNX2 mutations identified in patients with cleidocranial dysplasia

“…Another reason why the mutations might result in decreased transcriptional activity of RUNX2 could be impaired transport of the protein to the cell's nucleus. It has been previously shown that RUNX2 contains a Nuclear Localization Signal (NLS) downstream of the Runt domain (PRRHRQKLD) that, when defective, causes the accumulation of RUNX2 in the cytoplasm . Since one of the identified mutations, Δe4 c.580+1G>T (IVS3+1G > T), resulted in the absence of 35 aa spanning the Runt domain and a part of NLS (Figure ), we tested the effect of that mutation on the nuclear translocation of RUNX2.…”

A novel RUNX2 mutation in exon 8, G462X, in a patient with Cleidocranial Dysplasia

“…Although there have been numerous genetic studies about CCD in Asian populations, there are only three case reports or genetic studies of Korean CCD patients . Kim et al identified four novel Runx2 mutations in 11 Korean CCD patients (Q50X, E112X, R131G in exon 2, and an exon 1 slice donor site mutation).…”

“…5,6 Until now, more than 80 mutations in Runx2 gene have been identified, 7 most of which are missense mutations in the Runt domain. 8 Although there have been numerous genetic studies about CCD in Asian populations, [9][10][11][12][13][14][15][16] there are only three case reports or genetic studies of Korean CCD patients. 2,17,18 Kim et al 2 identified four novel Runx2 mutations in 11 Korean CCD patients (Q50X, E112X, R131G in exon 2, and an exon 1 slice donor site mutation).…”