Most babies with osteogenesis imperfecta Type II, the perinatal lethal form, have expressed mutations of the COL1A1 or COL1A2 genes. 7,8,15 The Type I collagen-producing cells synthesize approximately equal amounts of the normal and mutant collagen mRNAs and protein chains. For expressed mutations of the COL1A2 gene, approximately 50% of the Type I collagen molecules contain one normal pro-[alpha]2(I) chain whereas the other 50% contain one mutant pro-[alpha]2(I) chain. Some of the mutant molecules are degraded so the concentration of Type I collagen in the tissue is reduced. The remainder of the mutant Type I collagen is incorporated into the ECM where it impairs the structure and function of the tissue. 6 For expressed mutations of the COL1A1 gene, approximately 75% of the Type I collagen molecules contain one or two mutant pro-[alpha]1(I) chains. As with the COL1A2 mutations, variable proportions of the mutant molecules are degraded or incorporated into the ECM. A major deletion within one allele of the COL1A1 gene was the first reported mutation in a baby with osteogenesis imperfecta Type II. 18 A mutation of this type seemed to fit well with the severe phenotype of the baby. However, a subsequent study showed that the mutations more commonly produced single amino acid substitutions or small peptide deletions in the pro-[alpha]1(I) or pro-[alpha]2(I) chains. 15 The production of transgenic mouse models of osteogenesis imperfecta confirmed that one glycine substitution was sufficient to produce the disease. 77 The glycine substitutions identified in humans with osteogenesis imperfecta Type II involve one of the more than 300 glycine residues that occupy every third position of the triple helical domain of each collagen chain. These glycine residues are included in repeating Gly-X-Y triplets in which X and Y can be any amino acid. Substitution of glycine, the smallest amino acid, by other amino acids such as arginine, cysteine, serine and alanine, impairs the formation and stability of the collagen triple helix. Autosomal recessive inheritance initially was proposed as the mechanism responsible for the birth of multiple affected babies with osteogenesis imperfecta Type II in families with clinically healthy parents. 74 However, most babies were heterozygous rather than homozygous for their mutation. 15 The recurrence of osteogenesis imperfecta in the families was shown to be caused by DNA mosaicism in one parent. 19 The parent with mosaicism, who usually was healthy clinically, carried the mutation in a small number of their gonadal and somatic cells. Because of the occurrence of genetic mosaicism in some families, the overall risk of recurrence of osteogenesis imperfecta Type II is approximately 7% with each pregnancy. 19 Many individuals with osteogenesis imperfecta Types IB, III, IVA, and IVB have expressed COL1A1 or COL1A2 mutations similar to those in babies with osteogenesis imperfecta Type II. 15 Studies of genotype-phenotype correlation have shown that the severity of the osteogenesis imperfecta phenotype generally is worse if the mutation is expressed, with the production of a mutant protein, than if the mutation is not expressed. 15 The expressed osteogenesis imperfecta mutations alter the amino acid sequences of the main helical domain or the carboxy-terminal domain of the pro-[alpha]1(I) or pro-[alpha]2(I) chains of Type I procollagen. However, the severity of the osteogenesis imperfecta phenotype correlates poorly with the type and site of the expressed mutations. Specific types of mutations of the Type I collagen genes also can produce Ehlers-Danlos syndrome, a tissue laxity syndrome. Some individuals with the Type VII form of the syndrome, with multiple joint dislocations and mild skeletal fragility, are heterozygous for mutations involving exon 6 of the COL1A1 or COL1A2 genes. 17,24,31,84 These mutations result in the loss of a peptide bond that normally is cleaved during the removal of the amino-propeptide of the Type I procollagen chains in the conversion of procollagen to collagen. No expressed mutations involving the aminopropeptides of Type I collagen have been reported in patients with osteogenesis imperfecta. 15 Some individuals with the classic Type I form of Ehlers-Danlos syndrome, with joint laxity and scarred, fragile, and stretchy skin have mutations of an arginine amino acid residue in the helical domain of the pro-[alpha]1(I) chain. 55 The arginine residue, which normally occupies the X position of one of the Gly-X-Y triplets, is replaced by cysteine. Amino acid substitutions involving the X or Y positions of the numerous Gly-X-Y triplets within the main triple helix have not been reported in patients with osteogenesis imperfecta. Additional studies are needed to obtain a clearer understanding of the factors that contribute to the type and severity of osteogenesis imperfecta, Ehlers-Danlos syndrome, or mixed phenotypes resulting from mutations of the COL1A1 and COL1A2 genes.