Novel RUNX2 frameshift mutations in Chinese patients with cleidocranial dysplasia

Authors

  • Yanyu Huang,

    1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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  • Yaling Song,

    1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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  • Chenzheng Zhang,

    1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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  • Guoxin Chen,

    1. Department of Orthodontics, Hubei-MOST KLOS & KLOBM, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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  • Shihua Wang,

    1. Department of Stomatology, People's Hospital of Shayang, Jingmen, China
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  • Zhuan Bian

    Corresponding author
    1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
    • Zhuan Bian, The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China

      E-mail: bz@whuss.com

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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.

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