Identification of a novel COL1A1 frameshift mutation, c.700delG, in a Chinese osteogenesis imperfecta family.

Xiran Wang,Juming Lu,Jian Li,Yu Pei,Jingtao Dou,Zhaohui Lv

doi:10.1590/s1415-475738120130336

Xiran Wang, Juming Lu + Show 4 more

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https://doi.org/10.1590/s1415-475738120130336

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Abstract

Osteogenesis imperfecta (OI) is a family of genetic disorders associated with bone loss and fragility. Mutations associated with OI have been found in genes encoding the type I collagen chains. People with OI type I often produce insufficient α1-chain type I collagen because of frameshift, nonsense, or splice site mutations in COL1A1 or COL1A2. This report is of a Chinese daughter and mother who had both experienced two bone fractures. Because skeletal fragility is predominantly inherited, we focused on identifying mutations in COL1A1 and COL1A2 genes. A novel mutation in COL1A1, c.700delG, was detected by genomic DNA sequencing in the mother and daughter, but not in their relatives. The identification of this mutation led to the conclusion that they were affected by mild OI type I. Open reading frame analysis indicated that this frameshift mutation would truncate α1-chain type I collagen at residue p263 (p.E234KfsX264), while the wild-type protein would contain 1,464 residues. The clinical data were consistent with the patients’ diagnosis of mild OI type I caused by haploinsufficiency of α1-chain type I collagen. Combined with previous reports, identification of the novel mutation COL1A1-c.700delG in these patients suggests that additional genetic and environmental factors may influence the severity of OI.

Highlights

Osteogenesis imperfecta (OI), known as brittle bone disease (Marini et al, 2007), is a group of rare heritable connective tissue disorders characterized by skeletal fractures with mild trauma, secondary deformities, and extraskeletal manifestations (Ben Amor et al, 2011; Marini et al, 2007)
Mutations in COL1A1 and COL1A2 account for approximately 90% of OI cases and usually occur in patients with OI types I-IV
OI symptoms can occur in patients with mutations in genes that code proteins that interact with type I collagen, including cartilage associated protein (CRTAP; Starman et al, 1989; Barnes et al, 2006; Morello et al, 2006; Valli et al, 2012), prolyl-3-hydroxylase 1 (P3H1/LEPRE1), cyclophillin B (PPIB; Morello et al, 2006; Fratzl-Zelman et al, 2010; Marini et al, 2010; Valli et al, 2012; Zhang et al, 2012), FKBP10 (Barnes et al, 2012), WNT-1 (Pyott et al, 2013), and serpin peptidase inhibitor clade F member 1 (SERPINF1, Homan et al, 2011)

Summary

Introduction

Osteogenesis imperfecta (OI), known as brittle bone disease (Marini et al, 2007), is a group of rare heritable connective tissue disorders characterized by skeletal fractures with mild trauma, secondary deformities, and extraskeletal manifestations (Ben Amor et al, 2011; Marini et al, 2007). Such manifestations may include blue sclerae, progressive hearing loss, dentinogenesis imperfecta, and hyperlaxity of ligaments and skin (Ben Amor et al, 2011; Marini et al, 2007). OI severity ranges from intrauterine fractures and perinatal lethality to ex-

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