Expansion of polyalanine tracts in the QA domain may play a critical role in the clavicular development of cleidocranial dysplasia.

Abstract

Cleidocranial dysplasia (CCD) is an autosomal-dominant inheritable disease which is secondary to haploinsufficiency of the transcription factor runt-related transcription factor 2 (RUNX2). During the past 10 years, additional cases of RUNX2 mutation have been identified in nearly 500 families with CCD, including familial and sporadic cases (Otto et al. 2002). Some degree of clavicular hypoplasia is the most consistent feature of the disease and is often opposed at the mid line (Tang et al. 2007), while complete absence is rare and complicated to explain the specific mechanism. RUNX2, which is mapped to chromosome 6p21, was identified as the CCD causative gene in 1997 (Mundlos et al. 1997). This gene is the key transcription factor for osteoblastic differentiation, chondrocyte maturation and skeletal morphogenesis (Komori et al. 1997). Moreover, stability of RUNX2 protein, regulated by CBFb, is required for skeletal development by regulating chondrocyte differentiation, proliferation and osteoblast differentiation (Qin et al. 2014). RUNX2-deficient mice displayed impaired bone development manifestation as wide sutures, decreased bone ossification and hypoplastic clavicles (Kundu et al. 2002). RUNX2 consists of eight coding exons and spans a genomic region of 130 kb. According to the analysis of the protein structure, RUNX2 has several functional domains: QA domain, runt domain, nuclear localization signal (NSL), PST domain, VWRPY and nuclear matrix targeting sequence (NMTS). The QA domain, a stretch of 23 polyglutamine and 17 polyalanine tracts, is located in the N-terminus of RUNX2. An in vitro mutagenesis study showed that the QA domain prevented CBFb from binding to RUNX2. Deletionof the QA domain resulted in a four-fold decrease