Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: ... Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.
Cabral et al. (2007) described 5 patients with a lethal/severe osteogenesis imperfecta-like bone dysplasia caused by mutation in the LEPRE1 gene. The phenotype of the probands overlapped Sillence lethal type II/severe type III osteogenesis imperfecta (see 166210 and ... Cabral et al. (2007) described 5 patients with a lethal/severe osteogenesis imperfecta-like bone dysplasia caused by mutation in the LEPRE1 gene. The phenotype of the probands overlapped Sillence lethal type II/severe type III osteogenesis imperfecta (see 166210 and 259440), with severe osteoporosis, shortened long bones, and a soft skull with wide open fontanel. However, in contrast to the classic blue sclerae, triangular face, and narrow thorax of severe and lethal osteogenesis imperfecta, their probands had white sclerae, a round face, and a short barrel-shaped chest. Prenatal radiographs demonstrated gracile, undermineralized ribs and long bones. Multiple fractures were present at birth. Long bone radiographs of surviving probands showed bulbous metaphyses and apparent matrix disorganization. Their hands appeared relatively long compared to their forearms, with long phalanges, short metacarpals, and disorganized matrix. Vertebral compression fractures occurred in 2 of the surviving probands by 14 months and 5 years of age, respectively. Their bone density was lower than almost all individuals with severe osteogenesis imperfecta. Four probands, including the 3 lethal cases, were African, African American, or Afro-Caribbean. The fifth proband was Pakistani. The parents of proband 1 denied consanguinity and had a previous affected child who died in Africa; the parents of proband 2 had a second affected child.
By linkage studies, Wallis et al. (1993) excluded the COL1A1 and COL1A2 (120160) loci as the site of the mutation in this form of osteogenesis imperfecta; the combined lod scores were -10.6 for COL1A1 and -11.2 for COL1A2. ... By linkage studies, Wallis et al. (1993) excluded the COL1A1 and COL1A2 (120160) loci as the site of the mutation in this form of osteogenesis imperfecta; the combined lod scores were -10.6 for COL1A1 and -11.2 for COL1A2. Furthermore, they examined the type I procollagen produced by skin fibroblast cultures derived from 15 affected and 12 unaffected subjects from the 8 families studied by linkage plus 1 further family; no evidence for defects in the synthesis, structure, secretion, or posttranslational modification of the chains of type I procollagen was found. Prolyl 3-hydroxylase 1 (P3H1), the product of the LEPRE1 gene, hydroxylates a single proline, pro986 of the collagen type I alpha-1 chain (COL1A1; 120150) and forms a complex with cartilage-associated protein (CRTAP; 605497) and cyclophilin B (123841). Because the enzymatic activity in the 3-hydroxylation complex resides in P3H1, Cabral et al. (2007) postulated that its absence would result in severe bone dysplasia. They screened individuals with lethal/severe osteogenesis imperfecta-like bone dysplasia and overmodified collagen but without a type I collagen mutation detected by complete cDNA sequencing of both collagen chains. Real-time RT-PCR of total fibroblast RNA identified 5 individuals, 3 with lethal and 2 with severe bone dysplasia, whose LEPRE1 mRNA was 5 to 21% that of normal controls. All 5 individuals carried LEPRE1 mutations on both alleles (610339.0001-610339.0004). A common mutant allele was found in the African and African American probands (610339.0001). Willaert et al. (2009) screened the LEPRE1, CRTAP, and PPIB (123841) genes in 20 severe/lethal OI patients who were negative for mutation in type I collagen genes, and identified 4 homozygous and compound heterozygous mutations in the LEPRE1 gene in 4 probands, respectively (610339.0005-610339.0007). No mutations were found in CRTAP or PPIB. Two of the patients were relatively long-lived (alive at 17 years and 8 years of age, respectively). The authors noted that although at birth, clinical and radiologic features of these patients were virtually indistinguishable from those of patients with autosomal dominant severe/lethal OI, follow-up evaluation revealed the development of a severe osteochondrodysplasia with distinctive features, including complete disappearance of the honeycomb-type trabecular agglomeration, extreme osteoporosis, and additional widening of the rhizomelic diaphyses, accompanied by progressive narrowing and bowing of the mesomelic diaphysis, with reduction of the knee joint spaces to a mere line between the femora and tibiae.
To determined the carrier frequency of the LEPRE1 (1080+1G-T) mutation, Cabral et al. (2012) screened genomic DNA African American and African cohorts. Among 3,055 African Americans from the Mid-Atlantic United States tested, 12 carriers were identified for a ... To determined the carrier frequency of the LEPRE1 (1080+1G-T) mutation, Cabral et al. (2012) screened genomic DNA African American and African cohorts. Among 3,055 African Americans from the Mid-Atlantic United States tested, 12 carriers were identified for a frequency of 0.39% (1 in 255). Among Ghanaians, 9 carriers were found among 453 individuals for a frequency of 1.99% (1 in 50). Among Nigerians, 10 of 818 were carriers (1.22%, 1 in 182). Among total West Africans, 19 of 1,284 were carriers (1.48%, 1 in 68). The mutation was not detected in Africa outside of West Africa. Among 12 unrelated West African families with 16 independent mutant alleles, Cabral et al. (2012) identified a conserved haplotype surrounding the LEPRE1 gene extending from between D1S2861 to the region between markers STR3 and STR5. Using linkage disequilibrium analysis, Cabral et al. (2012) estimated the mutation to have originated 650 and 900 years before the present (1100 to 1350 CE).