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Mutational and structural characteristics of four novel heterozygous C-propeptide mutations in the proα1(I) collagen gene in Chinese osteogenesis imperfecta patients

Authors

  • Yanqin Lu,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Xiuzhi Ren,

    1. Department of Orthopaedic Surgery, The People's Hospital of Wuqing District, Tianjin, China
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  • Yanzhou Wang,

    1. Department of Paediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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  • Tianyou Li,

    1. Department of Paediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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  • Fuhui Li,

    1. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Shifu Wang,

    1. Department of Laboratory, Qilu Children's Hospital of Shandong University, Jinan, China
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  • Chao Xu,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Guohua Wu,

    1. Department of Paediatric Surgery, Langfang Red Cross Orthopedics Hospital, Langfang, China
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  • Hu Li,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Gongchao Li,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
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  • Fei Zhao,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Ziqiang Wang,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Xinkai Mo,

    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
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  • Jinxiang Han

    Corresponding author
    1. Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Key Laboratory for Virology of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China
    2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
    • Correspondence: Jinxiang Han, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, 18877 Jingshi Road, Jinan 250062, China. Tel.: 86-531-82919611; Fax: 86-531-82951586; E-mail: samshjx@sina.com

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  • Xiuzhi Ren and Yanzhou Wang contributed equally to this work.

Summary

Objective

Osteogenesis imperfecta (OI) with C-propeptide mutations in proα1(I) collagen gene are rarely reported. We report four novel C-propeptide mutations in COL1A1 gene from Chinese OI patients.

Methods

Clinical characteristics and radiographic findings were described for four OI patients with C-propeptide mutations in proα1(I) collagen gene. Mutations were identified by traditional DNA sequencing based on PCR. The locations of mutations were mapped, and in silico prediction was conducted to analyse their effects on protein structure. Histology studies of skin, bone and muscle tissues were performed.

Results

All four C-propeptide heterozygous mutations identified were in the COL1A1 gene. Heterozygous mutation of c.4021C>T (p.Q1341X) disrupted the chain recognition sequences and was found in patients with type IV OI. Mutations of c.3893C>A (p.T1298N) and c.3897C>A (p.C1299X) impeded the formation of disulphide bonds and were associated with type IV OI phenotype. Missense mutation of c.3835A>C (p.N1279H) disrupted Ca2+ binding and led to a severe type III OI phenotype. In silico programs predicted damaging effects for the patients with type III OI and the creation of an exonic splicing enhancer hexamer sequence for the type IV patients. Expansion of the bone marrow cavity and disorganization of osteocyte alignment was evident in bone specimens; and muscle atrophy and enlargement of intramuscular connective tissue were found in muscle specimens.

Conclusions

Four novel C-propeptide mutations in proα1(I) collagen gene were identified in Chinese OI patients, and their clinical severity ranged from moderate type IV to severe type III. In silico prediction of the mutation effect and histological characteristics of tissue specimens was in accordance with the OI phenotypes.

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