title: Two novel mutations in the PPIB gene cause a rare pedigree of osteogenesis imperfecta type IX.
abstract: BACKGROUND
  Osteogenesis imperfecta (OI) is a rare genetic skeletal disorder characterized by increased bone fragility and vulnerability to fractures. PPIB is identified as a candidate gene for OI-IX, here we detect two pathogenic mutations in PPIB and analyze the genotype-phenotype correlation in a Chinese family with OI.
  
  
  METHODS
  Next-generation sequencing (NGS) was used to screen the whole exome of the parents of proband. Screening of variation frequency, evolutionary conservation comparisons, pathogenicity evaluation, and protein structure prediction were conducted to assess the pathogenicity of the novel mutations. Sanger sequencing was used to confirm the candidate variants. RTQ-PCR was used to analyze the PPIB gene expression.
  
  
  RESULTS
  All mutant genes screened out by NGS were excluded except PPIB. Two novel heterozygous PPIB mutations (father, c.25A>G; mother, c.509G>A) were identified in relation to osteogenesis imperfecta type IX. Both mutations were predicted to be pathogenic by bioinformatics analysis and RTQ-PCR analysis revealed downregulated PPIB expression in the two carriers.
  
  
  CONCLUSIONS
  We report a rare pedigree with an autosomal recessive osteogenesis imperfecta type IX (OI-IX) caused by two novel PPIB mutations identified for the first time in China. The current study expands our knowledge of PPIB mutations and their associated phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis.
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, China.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Pan
authors.affiliation: Clinical Medicine, Grade 2014, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Human and Molecular Genetics, BCM (Baylor College of Medicine), One Baylor Plaza, Nab 2015, Houston, TX 77030, USA; AmCare Genomics Laboratory, Guangzhou 510300, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zishui
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Internal Medicine, The Second Affiliated Hospital, Fujian Medical University, Quanzhou 362000, China.
authors.forename: Chunmiao
authors.initials: C
authors.lastname: Guo
authors.affiliation: Fetal Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Weiying
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: guoyibin@mail.sysu.edu.cn.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D017124:Conserved Sequence; D021983:Cyclophilins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000073359:Exome Sequencing
chemical_list: C081786:cyclophilin B; D021983:Cyclophilins
keywords: Next-generation sequencing; Novel mutation; Osteogenesis imperfecta type IX; PPIB gene; Pathogenic identification