title: Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI.
abstract: 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 of SERPINF1 mutations 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 in SERPINF1 gene 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 in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.|Department of Cardiology, FuWai Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, 100037, China.
authors: Jian-Yi
authors: JY
authors: Wang
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Yi
authors: Y
authors: Liu
authors: Binhai Genomics Institute, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.|Tianjin Translational Genomics Center, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.
authors: Li-Jie
authors: LJ
authors: Song
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Fang
authors: F
authors: Lv
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Xiao-Jie
authors: XJ
authors: Xu
authors: Binhai Genomics Institute, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.|Tianjin Translational Genomics Center, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.
authors: A
authors: A
authors: San
authors: BGI-shenzhen, Shenzhen, 518083, China.|James D. Watson Institute of Genome Sciences, Hangzhou, 310058, China.
authors: Jian
authors: J
authors: Wang
authors: BGI-shenzhen, Shenzhen, 518083, China.|James D. Watson Institute of Genome Sciences, Hangzhou, 310058, China.
authors: Huan-Ming
authors: HM
authors: Yang
authors: Binhai Genomics Institute, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.|Tianjin Translational Genomics Center, BGI-Tianjin, BGI-shenzhen, Tianjin, 300308, China.
authors: Zi-Ying
authors: ZY
authors: Yang
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Yan
authors: Y
authors: Jiang
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Ou
authors: O
authors: Wang
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Wei-Bo
authors: WB
authors: Xia
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
authors: Xiao-Ping
authors: XP
authors: Xing
authors: Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China. limeilzh@sina.com.
authors: Mei
authors: M
authors: Li
mesh_terms: D000293:Adolescent; D015519:Bone Density / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010641:Phenotype; D015843:Serpins / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: Osteogenesis imperfecta; PEDF; SERPINF1 mutation; Type VI OI