title: Osteogenesis imperfecta and type-I collagen mutations. A lethal variant caused by a Gly910-->Ala substitution in the alpha 1 (I) chain.
abstract: In this study we describe a new dominant point mutation in COL1A1 causing a lethal form of Osteogenesis imperfecta (type II B). Dermal cultured fibroblasts from the proband were shown to produce both normal and heavily overmodified type-I collagen. The mutation introduced a local conformational perturbation, which causes abnormal exposure of arginine residues; the triple helical domain was susceptible to trypsin digestion even at 30 degrees C. The chains bearing the point mutation were poorly secreted and short-term pulse experiments showed that the extensive intracellular retention of mutant trimers also impaired the secretion of normal chains. The molecular defect was localized in a COL1A1 allele by cloning and sequencing a cDNA region corresponding to the CB6 peptide. A G to C transversion which causes the substitution in the triple helical region of Gly910 with alanine was found. The mutation also causes the disappearance of a MspI-recognition site at nucleotide 3263 of the pro alpha 1 (I) coding sequence. Restriction analysis, along with the biochemical screening of collagens, allowed us to perform prenatal diagnosis on cells from chorionic-villus sampling and to exclude the recurrence of the mutation in the sibling.
authors.affiliation: Dipartimento di Biochimica, Università di Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Valli
authors.forename: A
authors.initials: A
authors.lastname: Sangalli
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Mottes
authors.forename: A
authors.initials: A
authors.lastname: Forlino
authors.forename: R
authors.initials: R
authors.lastname: Tenni
authors.forename: P F
authors.initials: PF
authors.lastname: Pignatti
authors.forename: G
authors.initials: G
authors.lastname: Cetta
mesh_terms: D000409:Alanine / Q000235:genetics*; D003094:Collagen / Q000235:genetics*; D003488:Cyanogen Bromide; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005998:Glycine / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010449:Peptide Mapping; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D014357:Trypsin / Q000378:metabolism
chemical_list: D003094:Collagen; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D014357:Trypsin; D000409:Alanine; D003488:Cyanogen Bromide; D005998:Glycine