Osteogenesis imperfecta type II constitutes a disorder characterized by bone fragility, with many perinatal fractures, severe bowing of long bones, undermineralization, and death in the perinatal period due to respiratory insufficiency (Sillence et al., 1979; Barnes et al., ... Osteogenesis imperfecta type II constitutes a disorder characterized by bone fragility, with many perinatal fractures, severe bowing of long bones, undermineralization, and death in the perinatal period due to respiratory insufficiency (Sillence et al., 1979; Barnes et al., 2006). Also see osteogenesis imperfecta type VII (610682), an autosomal recessive form of lethal OI caused by mutation in the CRTAP gene (605497).
Morphologically there appear to be 2 forms of OI congenita, a thin-boned and a broad-boned type. The latter is well illustrated by the male and female sibs reported by Remigio and Grinvalsky (1970). The diagnosis is in question, ... Morphologically there appear to be 2 forms of OI congenita, a thin-boned and a broad-boned type. The latter is well illustrated by the male and female sibs reported by Remigio and Grinvalsky (1970). The diagnosis is in question, however, because one had dislocated lenses, aortic coarctation, and basophilic and mucoid changes in the connective tissue of the heart valves and aorta, while the other had less pronounced changes of the same nature in the aorta. Parental consanguinity was denied. Shapiro et al. (1982) suggested that the sibs reported by Remigio and Grinvalsky (1970) may have had another variant because of conspicuous extraskeletal features. The broad-bone type is also illustrated in Figure 8-3 by McKusick (1972) and the thin-bone type in Figure 8-5. The 'broad-bone' form of osteogenesis imperfecta and type IA achondrogenesis (200600) bear similarities. In the latter condition the ribs are thin and prone to fractures but the long bones of the limbs are severely shortened and bowed. In a study in Australia, Sillence et al. (1979) encountered a seemingly recessively inherited lethal perinatal OI with radiologically crumpled femora and beaded ribs--the 'broad-bone' type. By scanning electron microscopy, Levin et al. (1982) found no abnormality of the teeth in a case of OI congenita with death from pneumonia at age 10 months. Since abnormalities have been described in reported cases, these results may reflect heterogeneity in OI congenita. Levin et al. (1982) suggested that the case best fits OI type III of Sillence et al. (1979). They agreed with Sillence et al. (1979) that the term 'congenita' has limited usefulness since it merely indicates that fractures were present at birth--a feature that may occur in type I (166200), II, or III (259420). Elejalde and Mercedes de Elejalde (1983) observed a family in which the fourth child had OIC and died a few hours after birth, and OIC was diagnosed at 17 weeks' gestation in the fifth pregnancy by ultrasonography. Diagnosis was based on low echogenic properties of all bones, abnormally shaped skull and rib cage, distally thinned ribs, and short, deformed long bones with wide metaphyses and thin diaphyses. Radiographically the disorder reported by Buyse and Bull (1978) in 3 sibs (see 259410) was indistinguishable from Sillence's group A (see HISTORY), and chondroosseous histopathology was also identical; however, low birth weight, microcephaly, and cataracts were also present. The patients may, of course, have been homozygous for 2 separate but linked mutations or for a small chromosomal aberration. Byers et al. (2006) published practice guidelines for the genetic evaluation of suspected OI.
Bodian et al. (2009) screened DNA samples from 62 unrelated individuals with the perinatal lethal form of OI and identified COL1A1 or COL1A2 mutations in 59 samples and CRTAP or LEPRE1 (610339) mutations in 3 samples. The authors ... Bodian et al. (2009) screened DNA samples from 62 unrelated individuals with the perinatal lethal form of OI and identified COL1A1 or COL1A2 mutations in 59 samples and CRTAP or LEPRE1 (610339) mutations in 3 samples. The authors identified 61 distinct heterozygous mutations in the COL1A1 and COL1A2 genes, including 5 nonsynonymous rare variants of unknown significance. Sixty SNPs in the COL1A1 gene (including 17 novel variants) and 82 SNPs in COL1A2 (including 18 novel variants) were reported. Their findings suggested a frequency of 5% for CRTAP and LEPRE1 recessive mutations in severe/lethal OI. A computer model for predicting the outcome of glycine substitutions within the triple-helical domain of COL1A1 chains predicted lethality with 90% accuracy (26 of 29 mutations). Takagi et al. (2011) studied 4 Japanese patients, including 2 unrelated patients with what the authors called 'classic OI IIC' (see HISTORY) and 2 sibs with features of 'OI IIC' but less distortion of the tubular bones (OI dense bone variant). No consanguinity was reported in their parents. In both sibs and 1 sporadic patient, they identified heterozygous mutations in the C-propeptide region of COL1A1 (120150.0069 and 120150.0070, respectively), whereas no mutation in this region was identified in the other sporadic patient. Familial gene analysis revealed somatic mosaicism of the mutation in the clinically unaffected father of the sibs, whereas their mother and healthy older sister did not have the mutation. Histologic examination in the 2 sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyseal spongiosa. Thick, cartilaginous trabeculae (cartilaginous cores) were also found in the diaphyseal spongiosa. Chondrocyte columnization appeared somewhat irregular. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Takagi et al. (2011) concluded that heterozygous C-propeptide mutations in the COL1A1 gene may result in OI IIC with or without twisting of the long bones and that OI IIC appears to be inherited as an autosomal dominant trait.
In studies of material from the patient of Penttinen et al. (1975) and Heller et al. (1975), Williams and Prockop (1983) found deletion of about 500 bp in the gene for pro-alpha-1(I). See also Chu et al. (1983). ... In studies of material from the patient of Penttinen et al. (1975) and Heller et al. (1975), Williams and Prockop (1983) found deletion of about 500 bp in the gene for pro-alpha-1(I). See also Chu et al. (1983). This was probably the first characterization of a collagen gene defect. The deletion left coding sequences in register on either side. As a result, the mutant allele was expressed and half the pro-alpha-1 chains synthesized by fibroblasts were shortened by about 80 amino acids. Three-fourths of the procollagen trimers synthesized by fibroblasts contained either 1 or 2 shortened pro-alpha chains. The shortening was such that the presence of even 1 of the mutant pro-alpha-1 chains in a procollagen molecule prevented it from folding into a triple-helical configuration. Trimers containing 1 or 2 mutant pro-alpha-1 chains were rapidly degraded. Prockop (1984) called this 'protein suicide.' In further studies Chu et al. (1985) showed that the deletion eliminated 3 exons of the triple helical domain. The termini of the rearrangement were located within 2 short inverted repeats, suggesting that the self-complementary nature of these DNA elements favored formation of an intermediate that was the basis of the deletion. The patient's fibroblasts contained elevated type III collagen (120180) mRNA. The severity of the clinical presentation (with avulsion of the head and an arm during delivery) is explained. A null allele for pro-alpha-2 chains had much less deleterious effect (de Wet et al., 1983). Steinmann et al. (1982) and Steinmann et al. (1984) studied material from a male newborn with the lethal perinatal form of OI (and avulsion of an arm). The mother had the Marfan syndrome, as did several other members of the kindred including 2 sibs of the OI proband. The father was healthy and young. The infant's dermis was thinner and collagen fibrils were smaller in diameter than normal and fibroblasts showed dilated endoplasmic reticulum filled with granular material. Cultured fibroblasts synthesized 2 different species of pro-alpha-1(I) chains in about equal amounts. One chain was normal; the other contained cysteine in the triple-helical portion of the COOH-terminal cyanogen bromide peptide alpha-1(I)CB6. Collagen molecules that contained 2 copies of the mutant chain formed alpha-1(I)-dimers linked through interchain disulfide bonds. Molecules containing either 1 or 2 mutant chains were delayed in secretion and underwent excessive posttranslational modification with resulting increased lysyl hydroxylation and hydroxylysyl glycosylation. Delay in triple-helix formation seemed to be responsible for the increased modification. Neither parent had a demonstrable abnormality of collagen. The authors suspected a point mutation with substitution of cysteine for glycine. This may have been the first known example of a point mutation in a collagen gene (Steinmann, 1983). The role of the mother's Marfan syndrome is unclear; the molecular defect underlying the Marfan syndrome in this family had not been determined and it was not known whether the infant inherited the Marfan gene from the mother. The triple-helical domain of type I collagen contains no cysteine. It is made up of repeating triplets of amino acids Gly-X-Y where X and Y are any amino acid except tryptophan, tyrosine, and cysteine and most commonly proline and hydroxyproline, respectively. The fact that type III collagen contains cysteine (and tyrosine) in its triple-helical domain may indicate that its substitution for X or Y in type I collagen would not have as disruptive effects as observed here. In the lethal case thought by Steinmann et al. (1984) to represent a point mutation, Cohn et al. (1986) indeed found substitution of cysteine for glycine at position 988 of the triple-helical portion of half of the alpha-1(I) chains of type I collagen (120150.0018). The mutation disrupted the (G-X-Y)n pattern necessary for formation of the triple helix. This experiment of nature established the minimal mutation capable of producing lethal disease, and the lethality indicated the selective mechanism for stringent maintenance of collagen gene structure. A possibly high mutation rate for the OI II phenotype, which may be at least as frequent as 1 in 60,000 births, can be explained, even if most of them are dominants of the type described here. The COL1A1 gene may present a large target for lethal mutations because any change in the first 2 positions of the repeated GGN-NNN-NNN nucleotide sequence that encodes the triple-helical tripeptide Gly-X-Y is likely to be lethal if it occurs in the part of the gene encoding the carboxy-terminal half of the triple helix. Since the substitution of cysteine for glycine at position 988 of COL1A1 (120150.0018) was in the critical first position of the G-X-Y triplet, the mutation in the heterozygous state caused a lethal clinical picture. Sequence data confirmed that the mutation was a single base G-to-T change (Cohn et al., 1986). Conversely, Steinmann et al. (1986) found that the substitution of cysteine in the same domain of the alpha-1 chain in another family resulted in mild autosomal dominant OI (166200). The difference resulted from the fact that the substitution of cysteine was for X or Y rather than for G in the G-X-Y triplet.