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Mutation Spectrum and Genotype-phenotype Correlation in Chinese OI Patients

Author: XuChao
Tutor: LuYanQin
School: Jinan University
Course: Microbial and Biochemical Pharmacy
Keywords: Osteogenesis imperfecta Autosomal-dominant inheritance Type Icollagen COL1A1and COL1A2 Mutations detect Clinical feature
CLC: R681.1
Type: Master's thesis
Year: 2012
Downloads: 41
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BackgroundOsteogenesis imperfecta (OI) is a kind of rare genetic disease characterized bymesenchymal organization dysplasia and collagen formation obstacles. Clinicalsymptoms include bone fragile, blue sclera, dentinogenesis imperfecta (DI) andhearing loss. Individual incidence of OI is reported to be1/10000. Sillence classifiedOI into typeⅠ-Ⅳ on the basis of clinical symptoms in1979. Since then, type V-XIIof OI has been described and separated. OI is a genetic heterogeneity disease, patternsof inheritance are predominated by autosomal dominant. Collagen, type I, alpha1(COL1A1) and collagen, type I, alpha2(COL1A2), which encode α chains of type Iprocollagen, are the main OI-related autosomal dominant genes and relate toautosomal dominant OI. Mutations in these two genes lead to90%of OI cases. Inaddition, eight different genes defect associated with recessive genetic OI have beenreported in recent years. Cartilage-associated protein (CRTAP), leucineproline-enriched proteoglycan1(LEPRE1) and peptidylprolyl isomerase B (PPIB)encoding CRTAP, prolyl3-hydroxylase1(P3H1) and cyclophilins B (CyPB),respectively. They assemble into3-hydroxylation complex which participates inposttranslational modification of collagen I. As chaperones,65-kDa FK506-bindingprotein (FKBP65) which encoded by FK506-binding protein10(FKBP10) and heatshock protein47(HSP47) which encoded by serpin peptidase inhibitor, clade H1(SERPINH1) take part in the process of folding and assembling of collagen type I.Osterix (OSX) is a kind of transcription factor, which might be expected to play animportant role in osteoblast differentiation. Serpin peptidase inhibitor, clade F1 (SERPINF1) is responsible for the metabolic disorder of bone. Bone morphogeneticprotein1(BMP1) defect is reported to cause low levels of processing of collagen I.Procollagen-lysine,2-oxoglutarate5-dioxygenase2(PLOD2) gene was reported to bethe pathogenic gene for OI-Bruck syndrome. All above genes have been reported tobe related with autosomal recessive OI. Little was report about mutation spectrum ofOI Chinese people based on large population till now.ObjectiveThe study aims to build consortium for OI mutations in Chinese population andanalyze characteristics of autodominant and recessive OI mutation types..The secondaim of the study is to explore phenotype-genotype correlations preliminary.MethodsThe study was approved by Shandong Academy of Medical Sciences ReviewBoard. Peripheral bloods of clinical OI patients were collected under informedconsents. Genomic DNA was extracted from collected peripheral bloods. The codingregion and exon-intron boundaries of candidate genes were amplified by touch-downPCR program. DNA sequencing was conducted directly based on PCR product.Sequencing results were analyzed by Mutation Survery software in combination withmutation database for collagen type I (http://www.le.ac.uk/genetics/collagen/). To testmutation sites further, a cohort of200normal subjects was used to exclude potentialSNP sites. In silico prediction of pathogenic effect was performed using PolyPhen,Align GVGD, SIFT, NetGene2and BDGP softwares. For samples without mutationof COL1A1and COL1A2genes, LEPRE1, CRTAP, PPIB, FKBP10, OSX,SERPINH1, SERPINF1and PLOD2were further sequenced.ResultsIn all110Chinese OI patients’ testes, a total of61heterozygous mutations in61patients were detected. Seventeen patients were failed to identify any mutations in alltested OI relted genes in this study. Among61heterozygous mutaions, a singleheterozygous mutation in LEPRE1(c.1045G>A, p.Gly349Arg) gene was detected.The left60mutations were identified in either COL1A1or COL1A2gene,Twenty-nine novel mutation sites which were not recorded by mutation database for collagen type I and literatures. Missense mutation was the predominant mutationpatterns and its percentage was81%in COL1A1and93%in COL1A2generespectively. Nonsense and frameshift mutations were only identified in COL1A1inthis study. Exon37of COL1A1and exon19of COL1A2were the most high-riskregion which mutaions was much denser than other exons. Glycine substituion wasthe most common type of missense mutaions with the mutation rate as high as82%.There were a variety of glycine substituions, while Gly>Ser was the main substitutiontype, with the rate of54%. These results were in accordance with the results fromWestern populations. Five variants were identified in C-propeptide region of COL1A1,which was reported to carry more severe than variants in triple helix region.Interestingly, seven recurrent mutations in unrelated patients with differentphenotypes were discovered in this study. Four of these recurrent mutations may be‘hot-spot’ mutation sites. The effect of mutation on protein function was supported byin silico softwares predictions, either supported by one or some of diffent predictionsoftwares. Change of p.Gly1021Cys in COL1A2gene and p.Gly349Arg in LEPRE1gene were all tested to be damaging by PolyPhen, Align GVGD and SIFT softwares.ConclusionsGene diagnosis was conducted in110clinical Chinese OI patients. Mutationspectrum of COL1A1, COL1A2gene of Chinese OI patients was mapped. Oneheterozygous mutation of c.1045G>A in LEPRE1gene was discovered in this study.Seveteen samples failed to detect known OI genes and need to be further studied.

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CLC: > Medicine, health > Surgery > Orthopaedic Surgery ( movement system diseases,orthopedic surgery ) > Bone diseases > Dysplasia of bone
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