Osteogenesis imperfecta type I: second-trimester diagnosis and incidental identification of a dominant COL1A1 deletion mutation in the paucisymptomatic father.
We describe a three generation family with OI type I in which all affected members have one normal COL1A1 allele and another from which the intragenic Eco RI restriction site near the 3' end of the gene is missing.
Using PCR amplification of genomic DNA from affected individuals, followed by denaturing gradient gel electrophoresis (DGGE) and SSCP, we identified seven different COL1A1 gene mutations in eight unrelated families with OI type I.
Here we report the application of this COL1A1 null-allele detection test for prenatal diagnosis in a patient with OI type I in which it was shown that the fetus had inherited the normal COL1A1 allele from his affected mother and would not be affected with OI.
We have identified a 4 bp insertion in the 3' UTR of the COL1A1 gene localized downstream of the MnlI RFLP and used both markers in combination for the analysis of patients with OI type I.
Deletion of 19 base pairs in intron 13 of the gene for the pro alpha 2(I) chain of type-I procollagen (COL1A2) causes exon skipping in a proband with type-I osteogenesis imperfecta.
Some phenotype correlations, notably between the OI type IV phenotype and linkage to COL1A2 and between presenile hearing loss in OI type I and linkage to COL1A1, can be used to improve risk estimates substantially in families where there are no segregation data to distinguish whether COL1A1 or COL1A2 is the mutant locus.
Mutations identified in patients with OI type I lead to premature termination codons and allele-specific reductions of nuclear mRNA (termed nonsense-mediated mRNA decay or NMD), resulting in a COL1A1 null allele.
One caused a substitution of glycine 200 by valine at the N-terminus of D1 in OI type I/IV, lowering collagen stability by 50% at 34 degrees C. The other one was a substitution of valine 349 by phenylalanine at the C-terminus of D1 in OI type I, lowering collagen stability at 37.5 degrees C. Two other mutations, reported before, changed amino residues in D4.
Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found.