Osteogenesis Imperfecta, Type Xv

A number sign (#) is used with this entry because autosomal recessive osteogenesis imperfecta type XV (OI15) is caused by homozygous or compound heterozygous mutation in the WNT1 gene (164820) on chromosome 12q13.

Description

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.

Clinical Features

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.

Central Nervous System Features

Aldinger et al. (2016) reviewed the developmental outcomes and brain imaging studies of 6 patients with genetically confirmed OI15, including 5 previously reported patients. Five of 6 individuals had cerebellar hypoplasia that varied from mild hypoplasia to complete agenesis of the cerebellum, with frequent asymmetry. The 1 individual with normal brainstem and cerebellum size had severe Chiari malformation type 1. Three patients had hippocampal malformations, and 5 had a small midbrain, especially the tectum. Five of 6 patients had severe intellectual disability, and the sixth patient, with the Chiari malformation, had mild autism. All 5 patients with available data had a small head circumference, which was the most severe in the patient with total cerebellar agenesis (-3 SD). Care for these patients was challenging due to their profound disabilities and multiple fractures. Aldinger et al. (2016) suspected a relationship between severity of the intellectual disability and brainstem-cerebellar hypoplasia, but there were no apparent genotype/phenotype correlations.

Molecular Genetics

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).

Animal Model

The 'swaying' (sw) mouse, first described by Lane (1967), is characterized by rotational behavior and a severe cerebellar defect that is also present in some patients with OI. These mice are homozygous for a spontaneous 1-bp deletion (c.565delG) in the Wnt1 gene that results in a frameshift beginning at codon 189 and premature termination 10 codons downstream from the deletion (Thomas et al., 1991). Joeng et al. (2014) noted that the swaying mutation occurs in the same codon as an OI-linked nonsense mutation in human WNT1 (E189X; 164820.0003). Joeng et al. (2014) found that sw/sw mice developed major features of OI, including spontaneous fractures and severe osteopenia caused by decreased osteoblast activity. Biomechanical analysis showed that sw/sw bone had reduced strength compared with wildtype. Spectroscopic analysis suggested that the matrix of sw/sw bone had reduced mineral and collagen content compared with wildtype, a finding distinct from bone in collagen-related forms of OI. Joeng et al. (2014) concluded that the swaying mouse is a model of OI caused by WNT1 mutations.