1121J Med Genet 1992; 29: 112-118
The clinicopathological features of three babies with osteogenesis imperfecta resulting from the substitution of glycine by valine in the pro acl(I) chain of type I procollagen W G Cole, E Patterson, J Bonadio, P E Campbell, D W Fortune
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. W G Cole Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia. P E Campbell Department of Anatomical Pathology, Royal Women's Hospital, Melbourne, Australia. D W Fortune Howard Hughes Medical Institute and the Department of Pathology, The University of Michigan, Ann Arbor, Michigan 48109-0650, USA. E Patterson J Bonadio Correspondence
to
Professor Cole. Received 26 June 1991. Accepted 31 July 1991.
Abstract encodes the pro a2(I) chain of type I procollaThe features of three babies with peri- gen.' Mutations of the COLlAl gene alter the natal lethal osteogenesis imperfecta (OI structure of the main triple helical domain or, II) resulting from substitutions of glycine less frequently, the carboxy-propeptide extenby valine in the triple helical domain of sion of the pro alI(I) chain. In babies with the the al(I) chain of type I collagen were latter type of defect, the abnormal pro al(I) studied. The babies were heterozygous chains associate with other chains to form for this substitution at residue 1006 in mutant type I procollagen molecules that are case 1 (0135), 973 in case 2 (OI59), and 256 rapidly degraded.5 As a result, only a small in case 3 (OI7B). OI35 had the most severe amount of normal type I procollagen is secretclinical form, 01 IIC, with premature ed from cultured fibroblasts and the tissues rupture of membranes, severe ante- contain correspondingly small amounts of norpartum haemorrhage, stillbirth, severe mal type I collagen. In these babies, the OI II short limbed dwarfism, and extreme osteoporosis. OI59 was a better formed phenotype appears to be the result of a severe baby but was also born prematurely as a deficiency of normal type I collagen in the result of premature rupture of mem- tissues.6 Cultured fibroblasts from babies with helbranes and severe antepartum haemorical mutations produce normal type I procollarhage. She had the radiographic features of 01 IIA. OI7B was born at term and also gen and abnormal type I procollagen molechad the radiographic features of OI IIA. ules containing one or two mutant chains.78 Pathological examination of the skel- The mutant molecules are secreted less effietons of 0135 and OI59 showed grossly ciently than the normal ones and the level of deficient intramembranous and endo- intracellular collagen degradation is increased. chondral ossification. Trabecular bone In these babies, the OI II phenotype appears was sparse in the long bones and ver- to result from a deficiency of normal type I tebrae. The trabeculae contained a cartil- collagen and the presence of mutant type I age core and an overlying layer of woven collagen in the tissues.9 bone or osteoid. The diaphyses lacked Most of the structural mutations of the cortical bone. The periosteal fibroblasts triple helical domain of the acl(I) chain involve of OI35 contained grossly distended the substitution of a glycine residue in one of rough endoplasmic reticulum consistent the 338 Gly-X-Y repeating triplets.4 These with the 53% reduction in collagen secre- substitutions destabilise and delay the formation by cultured dermal fibroblasts. The tion of the triple helix, and allow excessive aorta, skin, and lungs were hypoplastic in post-translational hydroxylation and glycosylOI35 and OI59. The findings in this study ation of lysine residues on the amino-terminal show that glycine substitutions by valine side of the mutation.7 As a result, correlain Gly-X-Y triplets, from glycine 256 to tions have been sought between the type and glycine 1006, of the triple helical domain site of glycine substitutions and the resulting of al(I) chains produce the O II phenoglycine type. The phenotype was most severe in clinical phenotypes. The positionto of determine substitutions appears by cysteine the baby with the most carboxy-terminal the clinical phenotype while such correlations substitution. are less evident with other types of glycine substitutions.9 13 In this paper, we explore these relationships further in three babies with is a heterogenOsteogenesis imperfecta (OI) eous genetic disorder that produces bone OI II resulting from heterozygous substitufragility, abnormal blueness of the sclerae, tions of glycine by valine at positions 256,'1 dentinogenesis imperfecta, and premature 973,15 and 1006'5 of the triple helical domain of deafness.' There are four main clinical types of the al(I) chain. OI and the perinatal lethal type, type II OI or OI II, is the focus of this report.23 01 II usually results from heterozygous mutations of the COLlAl gene that encodes Case reports the pro a 1(I) chains and less frequently results The main details of the parents, pregnancies, from mutations of the COL1A2 gene that and babies are summarised in the table.
113
The clinicopathological features of three babies with osteogenesis imperfecta
Features of the parents, pregnancies, and babies. Features
OI35 (Gly 1006)
OI59 (Gly 973)
07B (Gly 256)
Father's age Mother's age Parity Gravida Gestation (w) Pregnancy
32 25 1 2 28 Large antepartum haemorrhage Vaginal Female
37 33 0 2 30
29 27 2 3 40 Normal
Delivery Sex Head circumference (cm) Crown-heel length (cm) Birth weight (g) Survival (days) Type of Olt
Large antepartum haemorrhage Caesarian section Female 24* 30* 1000*
26* 650* Stillborn IIC
* Value less than the 10th centile for an Australian hospital t Sillence classification.12
The clinicopathological features of three babies with osteogenesis imperfecta resulting from the substitution of glycine by valine in the pro acl(I) chain of type I procollagen W G Cole, E Patterson, J Bonadio, P E Campbell, D W Fortune
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. W G Cole Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia. P E Campbell Department of Anatomical Pathology, Royal Women's Hospital, Melbourne, Australia. D W Fortune Howard Hughes Medical Institute and the Department of Pathology, The University of Michigan, Ann Arbor, Michigan 48109-0650, USA. E Patterson J Bonadio Correspondence
to
Professor Cole. Received 26 June 1991. Accepted 31 July 1991.
Abstract encodes the pro a2(I) chain of type I procollaThe features of three babies with peri- gen.' Mutations of the COLlAl gene alter the natal lethal osteogenesis imperfecta (OI structure of the main triple helical domain or, II) resulting from substitutions of glycine less frequently, the carboxy-propeptide extenby valine in the triple helical domain of sion of the pro alI(I) chain. In babies with the the al(I) chain of type I collagen were latter type of defect, the abnormal pro al(I) studied. The babies were heterozygous chains associate with other chains to form for this substitution at residue 1006 in mutant type I procollagen molecules that are case 1 (0135), 973 in case 2 (OI59), and 256 rapidly degraded.5 As a result, only a small in case 3 (OI7B). OI35 had the most severe amount of normal type I procollagen is secretclinical form, 01 IIC, with premature ed from cultured fibroblasts and the tissues rupture of membranes, severe ante- contain correspondingly small amounts of norpartum haemorrhage, stillbirth, severe mal type I collagen. In these babies, the OI II short limbed dwarfism, and extreme osteoporosis. OI59 was a better formed phenotype appears to be the result of a severe baby but was also born prematurely as a deficiency of normal type I collagen in the result of premature rupture of mem- tissues.6 Cultured fibroblasts from babies with helbranes and severe antepartum haemorical mutations produce normal type I procollarhage. She had the radiographic features of 01 IIA. OI7B was born at term and also gen and abnormal type I procollagen molechad the radiographic features of OI IIA. ules containing one or two mutant chains.78 Pathological examination of the skel- The mutant molecules are secreted less effietons of 0135 and OI59 showed grossly ciently than the normal ones and the level of deficient intramembranous and endo- intracellular collagen degradation is increased. chondral ossification. Trabecular bone In these babies, the OI II phenotype appears was sparse in the long bones and ver- to result from a deficiency of normal type I tebrae. The trabeculae contained a cartil- collagen and the presence of mutant type I age core and an overlying layer of woven collagen in the tissues.9 bone or osteoid. The diaphyses lacked Most of the structural mutations of the cortical bone. The periosteal fibroblasts triple helical domain of the acl(I) chain involve of OI35 contained grossly distended the substitution of a glycine residue in one of rough endoplasmic reticulum consistent the 338 Gly-X-Y repeating triplets.4 These with the 53% reduction in collagen secre- substitutions destabilise and delay the formation by cultured dermal fibroblasts. The tion of the triple helix, and allow excessive aorta, skin, and lungs were hypoplastic in post-translational hydroxylation and glycosylOI35 and OI59. The findings in this study ation of lysine residues on the amino-terminal show that glycine substitutions by valine side of the mutation.7 As a result, correlain Gly-X-Y triplets, from glycine 256 to tions have been sought between the type and glycine 1006, of the triple helical domain site of glycine substitutions and the resulting of al(I) chains produce the O II phenoglycine type. The phenotype was most severe in clinical phenotypes. The positionto of determine substitutions appears by cysteine the baby with the most carboxy-terminal the clinical phenotype while such correlations substitution. are less evident with other types of glycine substitutions.9 13 In this paper, we explore these relationships further in three babies with is a heterogenOsteogenesis imperfecta (OI) eous genetic disorder that produces bone OI II resulting from heterozygous substitufragility, abnormal blueness of the sclerae, tions of glycine by valine at positions 256,'1 dentinogenesis imperfecta, and premature 973,15 and 1006'5 of the triple helical domain of deafness.' There are four main clinical types of the al(I) chain. OI and the perinatal lethal type, type II OI or OI II, is the focus of this report.23 01 II usually results from heterozygous mutations of the COLlAl gene that encodes Case reports the pro a 1(I) chains and less frequently results The main details of the parents, pregnancies, from mutations of the COL1A2 gene that and babies are summarised in the table.
113
The clinicopathological features of three babies with osteogenesis imperfecta
Features of the parents, pregnancies, and babies. Features
OI35 (Gly 1006)
OI59 (Gly 973)
07B (Gly 256)
Father's age Mother's age Parity Gravida Gestation (w) Pregnancy
32 25 1 2 28 Large antepartum haemorrhage Vaginal Female
37 33 0 2 30
29 27 2 3 40 Normal
Delivery Sex Head circumference (cm) Crown-heel length (cm) Birth weight (g) Survival (days) Type of Olt
Large antepartum haemorrhage Caesarian section Female 24* 30* 1000*
26* 650* Stillborn IIC
* Value less than the 10th centile for an Australian hospital t Sillence classification.12
