Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI
Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI
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DOI：
10.1007/s00223-016-0201-z
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发表时间：
2016-10
影响因子：
4.2
通讯作者：
Jian-yi Wang;Yi Liu;Li-jie Song;F. Lv;Xiao-jie Xu;A. San;Jian Wang;Huanming Yang;Zi-ying Yang;Yan Jiang;O. Wang;W. Xia;X. Xing;Mei Li
中科院分区：
文献类型：
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作者：
Jian-yi Wang;Yi Liu;Li-jie Song;F. Lv;Xiao-jie Xu;A. San;Jian Wang;Huanming Yang;Zi-ying Yang;Yan Jiang;O. Wang;W. Xia;X. Xing;Mei Li
成骨不全症是一组以复发性脆性骨折为特征的遗传性疾病。丝氨酸肽酶抑制剂，进化支F，成员1 （serinf1）是已知的导致一种独特的，极其罕见的常染色体隐性形式的VI型OI。在这里，我们首次报道了在中国成骨不全症患者中检测到serpinf1突变。我们设计了一种新的靶向性oi相关基因的下一代测序面板，用于鉴定致病性突变，并通过Sanger测序和共分离分析证实了这一结果。我们还通过评估骨密度、放射骨折、血清骨转换标志物和色素上皮衍生因子（PEDF）浓度来研究成骨不全患者的表型。本研究从5个不相关的家庭中招募了6名中度至重度骨脆性、明显低骨密度和严重四肢畸形的患者。发现6个致病突变inserpinf1基因，其中5个为新突变：(1)外显子3的纯合框内插入（c.271_279dup, p.Ala91_Ser93dup）；(2)内含子3 （c.283 + 1G > T，剪接位点）和外显子5 （c.498_499delCA, p.Arg167SerfsX35，移码位点）的复合杂合突变；(3)第8外显子纯合移码突变（c.1202_1203delCA, p.Thr401ArgfsX）；(4)外显子3出现复合杂合错义突变（c.184G > A, p.Gly62Ser）和框内插入（c.271_279dup, p.Ala91_Ser93dup）；(5)外显子4杂合无义突变(c.397C>T + ？p.Gln133X + ?)。几乎所有受试者的血清PEDF水平几乎检测不到。我们发现了5个新的突变inserpinf1，并首次证实了血清PEDF水平在中国极为罕见的i型成骨不全患者中的诊断价值。
Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection ofSERPINF1mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations inSERPINF1gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations inSERPINF1and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.