RUNX2 mutations in Taiwanese patients with cleidocranial dysplasia

Wei-De Lin,Chung-Hsing Wang,Yushin Tsai,Shuan-Pei Lin,Fuu-Jen Tsai,Chih-Ping Chen

doi:10.1590/s1415-47572011005000002

Abstract

Cleidocranial dysplasia (CCD) is an autosomal dominant human skeletal disorder comprising hypoplastic clavicles, wide cranial sutures, supernumerary teeth, short stature, and other skeletal abnormalities. It is known that mutations in the human RUNX2 gene mapped at 6p21 are responsible for CCD. We analyzed the mutation patterns of the RUNX2 gene by direct sequencing in six Taiwanese index cases with typical CCD. One of the patients was a familial case and the others were sporadic cases. Sequencing identified four mutations. Three were caused by single nucleotide substitutions, which created a nonsense (p.R391X), two were missense mutations (p.R190W, p.R225Q), and the forth was a novel mutation (c.1119delC), a one-base deletion. Real time quantitative PCR adapted to determine copy numbers of the promoter, all exons and the 3’UTR region of the RUNX2 gene detected the deletion of a single allele in a sporadic case. The results extend the spectrum of RUNX2 mutations in CCD patients and indicate that complete deletions of the RUNX2 gene should be considered in those CCD patients lacking a point mutation detected by direct sequencing.

Highlights

Cleidocranial dysplasia, (CCD, MIM#119600), is an autosomal dominant skeletal dysplasia comprising defective skull ossification with frontal bossing, open fontanels, clavicular hypoplasia, delayed ossification of the pelvis, late eruption of permanent teeth, malformed dental roots, supernumerary teeth, and normal intelligence (Mundlos, 1999)
RUNX2 knockout mice show a complete lack of bone formation, whereas heterozygous RUNX2 mutated mice display some of the hallmarks of human CCD, including open fontanelles and hypoplastic clavicles, but not the dental anomalies (Otto et al, 1997)
The mutation seen in Patient 4 was in heterozygosis and represented a C-to-T transition at nucleotide 568 in exon 1 of RUNX2, this causing the substituation of arginine by tryptophan at amino acid position 190 (p.R190W) in the runt domain (Otto et al, 2002)

Summary

Introduction

Cleidocranial dysplasia, (CCD, MIM#119600), is an autosomal dominant skeletal dysplasia comprising defective skull ossification with frontal bossing, open fontanels, clavicular hypoplasia, delayed ossification of the pelvis, late eruption of permanent teeth, malformed dental roots, supernumerary teeth, and normal intelligence (Mundlos, 1999). The runt domain interacts with the core binding factor consensus sequence TGT/CGGT located in the promoter region of target genes. The last five amino acids of RUNX2 (VWRPY) compose a conserved motif in all runt proteins (Quack et al, 1999; Zhang et al, 2000; Otto et al, 2002).

Results

Conclusion