Haplotype analysis of collagen type I genes in the general population and in osteogenesis imperfecta families.

The allele frequencies of 2 new polymorphic markers of collagen type I proalpha 1 (COL1A1) and proalpha 2 (COL1A2) genes were determined in a random sample of chromosomes by polymerase chain reaction. The minor allele frequencies were 0.27 for COL1A1/+88Mn1I, and 0.39 for COL1A2/1446 PvuII RFLPs, respectively. These 2 polymorphisms increased the combined (PIC) values we previously determined in the Italian population with Southern blotting procedures, from 0.71 at the COL1A1 locus to 0.81, and from 0.73 at the COL1A2 locus to 0.88, respectively. With a combination of these markers, we have carried out the segregation analysis of 4 new families in which osteogenesis imperfecta (OI) segregated as a dominant trait. The disease segregated with COL1A1 in 2 OI type I families, and with COL1A2 in one OI type IV family. In one OI type I family the concordant locus was uncertain. This analysis was extended to the 7 dominant OI families we previously reported: in 3 out of 11 pedigrees either locus still could not be excluded, indicating the need for more genetic markers. COL1A1 and COL1A2 haplotype frequencies were compared in normal and OI chromosomes: no preferential association of the disease with a given haplotype was detected. The correlation between affected locus and clinical aspects is discussed.