Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type I procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type I procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha1(I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.
On page 555 under the section titled Mutations in FKBP10 cause Recessive OI, there are two errors in the nomenclature for the identified mutations. The FKBP10 (NM_021939.3) mutation isolated in the Turkish cases (proband R06-113A) is c.321_353 del and is predicted to result in the deletion of eleven amino acids in the protein, p.Met107_Leu117 del. In the second paragraph of the subheading, the mutation in the Mexican-American family (proband R93-188) should be
Turkey has a high rate of consanguineous marriage (21.1%), indicating strong preference for this traditional form of marital union. Social and cultural factors are especially important in marriages between first and second cousins. Fertility is high, the closed birth interval is long, and the sterility rate is low among these couples. Post-neonatal, infant and under-5 mortalities are high in first cousin unions by comparison with non-consanguineous marriages. According to the results of the study, first cousin marriage is a significant determinant underlying the high total fertility and infant mortality rates in Turkey.
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