title: Two novel distinct COL1A2 mutations highlight the complexity of genotype-phenotype correlations in osteogenesis imperfecta and related connective tissue disorders.
abstract: Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype-phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype-phenotype correlation in genetic counselling in OI.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 10, 91054 Erlangen, Germany. Electronic address: miriam.reuter@uk-erlangen.de.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.forename: Georg C
authors.initials: GC
authors.lastname: Schwabe
authors.forename: Christian
authors.initials: C
authors.lastname: Ehlers
authors.forename: Christoph
authors.initials: C
authors.lastname: Marschall
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
mesh_terms: D002675:Child, Preschool; D018389:Codon, Nonsense; D024042:Collagen Type I / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D024042:Collagen Type I
keywords: COL1A2; Genotype–phenotype correlation; Osteogenesis imperfecta