title: Eight mutations including 5 novel ones in the COL1A1 gene in Czech patients with osteogenesis imperfecta.
abstract: OBJECTIVE
  Osteogenesis imperfecta (OI), also called brittle bone disease, is a clinically and genetically heterogeneous disorder characterized by decreased bone density. Autosomal dominant forms result from mutations in either the COL1A1 (collagen type I alpha-1 chain) or COL1A2 (collagen type I alpha-2 chain) genes encoding the type I collagen. The aim of this study was to identify mutations and allelic variants of the COL1A1 gene in patients with osteogenesis imperfecta (OI).
  
  
  RESULTS
  Molecular genetic analysis of the COL1A1 gene was performed in a cohort of 34 patients with OI. The DNA samples were analysed by PCR and Sanger sequencing. DNA changes in coding sequences of the gene were compared with Type 1 Collagen Mutation Database. Genetic variants resulting in either quantitatively or structurally defective protein production were found in 6 unrelated patients. Four identified mutations are connected to decreased protein production (Tyr47X, Arg131X, Arg415X, Gln1341X), 2 result in amino acid substitution (Cys61Phe, Pro1186Ala) and the last affects splicing (c.1057-1G>T). Further, one silent mutation (Gly794Gly) was detected. No protein analysis was performed.
  
  
  CONCLUSIONS
  Of the 8 identified mutations, 5 were novel and have not been reported before. Only one causes substitution of glycine located within the Gly-X-Y triplets in the triple helical domain. Two mutations are located in major ligand binding regions (MLBR) which are important for bone strength and flexibility. Although the genotype-phenotype correlation is still unclear, our findings should contribute to elucidating this relationship in patients diagnosed with OI.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Hruskova
authors.affiliation: Centre of Medical Genetics, Antwerp University and University Hospital, Antwerp, Belgium.
authors.forename: Igor
authors.initials: I
authors.lastname: Fijalkowski
authors.affiliation: Centre of Medical Genetics, Antwerp University and University Hospital, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.affiliation: Ambulant Centre for Defects of Locomotor Apparatus 1.1.c., Prague, Czech Republic.|Faculty of Medical Studies, West Bohemia University, Pilsen, Czech Republic.
authors.forename: Ivo
authors.initials: I
authors.lastname: Marik
authors.affiliation: Centre of Medical Genetics, Antwerp University and University Hospital, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Martasek
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Mazura
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D002648:Child; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: C000716127:COL1A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005998:Glycine
keywords: COL1A1; collagen type I; mutations; osteogenesis imperfecta