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). Keupp et al. (2013) and Pyott et al. (2013) described osteogenesis imperfecta type XV, an autosomal recessive form of the disorder characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclera. Tooth development and hearing are normal. Learning and developmental delays and brain anomalies have been observed in some patients.
Keupp et al. (2013) described 3 individuals from 2 different branches of a consanguineous Turkish family who had typical clinical features of OI, including early-onset recurrent fractures, bone deformity, significant reduction of bone density, and short stature. Two ... Keupp et al. (2013) described 3 individuals from 2 different branches of a consanguineous Turkish family who had typical clinical features of OI, including early-onset recurrent fractures, bone deformity, significant reduction of bone density, and short stature. Two had bluish sclerae. Tooth development and hearing were normal. One had brain malformations and developmental delay. Keupp et al. (2013) described 4 other consanguineous families with varying clinical severity of OI, ranging from moderate to progressively deforming. Pyott et al. (2013) reported 4 families segregating moderately severe to progressive forms of OI similar to OI type III. In 3 of the families, the affected individuals also had learning and developmental delays, and 2 affected individuals from different families had brain malformations. Fahiminiya et al. (2013) described 4 individuals from 3 families with a form of OI consistent with OI type IV. All of those affected had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life.
By whole-exome sequencing and homozygosity mapping in affected members of a consanguineous Turkish family segregating OI, Keupp et al. (2013) identified a homozygous 1-bp duplication (c.859dupC; 164820.0001) in the WNT1 gene. Keupp et al. (2013) sequenced the entire ... By whole-exome sequencing and homozygosity mapping in affected members of a consanguineous Turkish family segregating OI, Keupp et al. (2013) identified a homozygous 1-bp duplication (c.859dupC; 164820.0001) in the WNT1 gene. Keupp et al. (2013) sequenced the entire WNT1 coding region in 11 additional families with autosomal recessive OI for which all known genes affected in OI had been excluded and identified 4 additional homozygous mutations in 4 families (see, e.g., c.624+4A-G, 164820.0002 and E189X, 164820.0003). Keupp et al. (2013) demonstrated that altered WNT1 proteins failed to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling. In addition, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. In affected members of 4 consanguineous families segregating a moderately severe and progressive form of OI, Pyott et al. (2013) identified 5 different mutations in the WNT1 gene in homozygous or compound heterozygous state (see, e.g., 164820.0004). In 4 affected children from 3 unrelated families segregating OI, Fahiminiya et al. (2013) identified 4 different mutations in the WNT1 gene in homozygous or compound heterozygous state (see, e.g., 164820.0005-164820.0006). In 2 Lao Hmong sisters with a severe form of osteogenesis imperfecta, Laine et al. (2013) identified a homozygous nonsense mutation in the WNT1 gene (S295X; 164820.0008). Both parents were heterozygous for the mutation. The 44-year-old mother had normal bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA) and normal spinal radiographs. The 43-year-old father had normal femoral BMD but had a z score of 1.8 for BMD of the lumbar spine (vertebral bodies L1 through L4). His height was normal (160 cm). His spinal radiographs showed a mild compression deformity involving the superior end plate of the L5 vertebral body. Laine et al. (2013) demonstrated that, in vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. Laine et al. (2013) also showed that mouse Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in OI type XV and in osteoporosis (615521).