Cleidocranial dysplasia: clinical and molecular genetics.
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Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. The disease gene has been mapped to chromosome 6p21 within a region containing CBFA1, a member of the runt family of transcription factors. Mutations in the CBFA1 gene that presumably lead to synthesis of an inactive gene product were identified in patients with CCD. The function of CBFA1 during skeletal development was further elucidated by the generation of mutated mice in which the Cbfa1 gene locus was targeted. Loss of one Cbfa1 allele (+/-) leads to a phenotype very similar to human CCD, featuring hypoplasia of the clavicles and patent fontanelles. Loss of both alleles (-/-) leads to a complete absence of bone owing to a lack of osteoblast differentiation. These studies show that haploinsufficiency of CBFA1 causes the CCD phenotype. CBFA1 controls differentiation of precursor cells into osteoblasts and is thus essential for membranous as well as endochondral bone formation. (+info)
Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia.
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Cleidocranial dysplasia (CCD) is a dominantly inherited disorder characterized by patent fontanelles, wide cranial sutures, hypoplasia of clavicles, short stature, supernumerary teeth, and other skeletal anomalies. We recently demonstrated that mutations in the transcription factor CBFA1, on chromosome 6p21, are associated with CCD. We have now analyzed the CBFA1 gene in 42 unrelated patients with CCD. In 18 patients, mutations were detected in the coding region of the CBFA1 gene, including 8 frameshift, 2 nonsense, and 9 missense mutations, as well as 2 novel polymorphisms. A cluster of missense mutations at arginine 225 (R225) identifies this residue as crucial for CBFA1 function. In vitro green fluorescent protein fusion studies show that R225 mutations interfere with nuclear accumulation of CBFA1 protein. There is no phenotypic difference between patients with deletions or frameshifts and those with other intragenic mutations, suggesting that CCD is generally caused by haploinsufficiency. However, we were able to extend the CCD phenotypic spectrum. A missense mutation identified in one family with supernumerary teeth and a radiologically normal skeleton indicates that mutations in CBFA1 can be associated exclusively with a dental phenotype. In addition, one patient with severe CCD and a frameshift mutation in codon 402 had osteoporosis leading to recurrent bone fractures and scoliosis, providing first evidence that CBFA1 may help maintain adult bone, in addition to its function in bone development. (+info)
CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.
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Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1. To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families. The majority of mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene. These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency. We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth. Functional studies show that two of the three mutations were hypomorphic in nature and two were associated with significant intrafamilial variable expressivity, including isolated dental anomalies without the skeletal features of CCD. Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD and isolated primary dental anomalies. (+info)
The developmental control of osteoblast-specific gene expression: role of specific transcription factors and the extracellular matrix environment.
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Bone formation is a carefully controlled developmental process involving morphogen-mediated patterning signals that define areas of initial mesenchyme condensation followed by induction of cell-specific differentiation programs to produce chondrocytes and osteoblasts. Positional information is conveyed via gradients of molecules, such as Sonic Hedgehog that are released from cells within a particular morphogenic field together with region-specific patterns of hox gene expression. These, in turn, regulate the localized production of bone morphogenetic proteins and related molecules which initiate chondrocyte- and osteoblast-specific differentiation programs. Differentiation requires the initial commitment of mesenchymal stem cells to a given lineage, followed by induction of tissue-specific patterns of gene expression. Considerable information about the control of osteoblast-specific gene expression has come from analysis of the promoter regions of genes encoding proteins like osteocalcin that are selectively expressed in bone. Both general and tissue-specific transcription factors control this promoter. Osf2/Cbfa1, the first osteoblast-specific transcription factor to be identified, is expressed early in the osteoblast lineage and interacts with specific DNA sequences in the osteocalcin promoter essential for its selective expression in osteoblasts. The OSF2/CBFA1 gene is necessary for the development of mineralized tissues, and its mutation causes the human disease, cleidocranial dysplasia. Committed osteoprogenitor cells already expressing Osf2/Cbfa1 must synthesize a collagenous ECM before they will differentiate. A cell:ECM interaction mediated by integrin-type cell-surface receptors is essential for the induction of osteocalcin and other osteoblast-related proteins. This interaction stimulates the binding of Osf2/Cbfa1 to the osteocalcin promoter through an as-yet-undefined mechanism. (+info)
Early prenatal ultrasound diagnosis of cleidocranial dysplasia.
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A woman was referred in the first trimester of her third pregnancy because of a family history of cleidocranial dysplasia. An ultrasound examination at 14 weeks 4 days revealed a fetus with appropriate biometric measurements. However, the clavicles were noted to be hypoplastic and the cranium appeared less well ossified than expected for gestational age, suggesting the diagnosis of cleidocranial dysplasia. On subsequent examination at 21 weeks, the findings were essentially unchanged. Induced vaginal delivery owing to decreased amniotic fluid volume occurred at 37 weeks, and a female weighing 3200 g was delivered. The infant had clinical and X-ray signs of cleidocranial dysplasia. (+info)
The 'chef's hat' appearance of the femoral head in cleidocranial dysplasia.
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Cleidocranial dysplasia (CCD) is inherited as an autosomal dominant disorder characterised by failure of membranous ossification. The condition is due to a mutation of the cbfa1 gene on chromosome 6 which has a role in the development of osteoblasts from the mesenchymal cells. In their growing years, these patients have an unusual shape of the femoral head reminiscent of a 'chef's hat'. In order to confirm the consistency of this sign, we have reviewed the radiographs of 28 patients with CCD. All except three had this appearance. The sign was also seen in patients with coxa vara associated with a variety of other conditions. The chef's hat sign may occur secondary to the particular mechanical environment created by coxa vara as well as abnormal cellular function in patients with CCD. Although coxa vara has some influence on the shape of the femoral head, it is not entirely responsible for its morphology since it was present in only six of the 28 patients with CCD. (+info)
A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia.
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Cleidocranial dysplasia (CCD), an autosomal-dominant human bone disease, is thought to be caused by heterozygous mutations in runt-related gene 2 (RUNX2)/polyomavirus enhancer binding protein 2alphaA (PEBP2alphaA)/core-binding factor A1 (CBFA1). To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, CCDalphaA376, originally identified in a CCD patient. The nonsense mutation, which resulted in a truncated RUNX2 protein, severely impaired RUNX2 transactivation activity. We show that signal transducers of transforming growth factor beta superfamily receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance the transactivation ability of this factor. The truncated RUNX2 protein failed to interact with and respond to Smads and was unable to induce the osteoblast-like phenotype in C2C12 myoblasts on stimulation by bone morphogenetic protein. Therefore, the pathogenesis of CCD may be related to the impaired Smad signaling of transforming growth factor beta/bone morphogenetic protein pathways that target the activity of RUNX2 during bone formation. (+info)
Cbfa1: a molecular switch in osteoblast biology.
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During the past 4 years, our molecular understanding of osteoblast biology has made rapid progress due to the characterization of the function of one molecule, Cbfa1. This member of the runt/Cbfa family of transcription factors was first identified as the nuclear protein binding to an osteoblast-specific cis-acting element activating the expression of Osteocalcin, the most osteoblast-specific gene. Cbfa1 was then shown to regulate the expression of all the major genes expressed by osteoblasts. Consistent with this ability, genetic experiments identified Cbfa1 as a key regulator of osteoblast differentiation in vivo. Indeed, analysis of Cbfa1-deficient mice revealed that osteoblast differentiation is arrested in absence of Cbfa1, demonstrating both that it is required for this process and that no parallel pathway can overcome its absence. The importance of Cbfa1 in controlling osteoblast differentiation was further emphasized by the identification of Cbfa1 haploinsufficiency as the cause of cleidocranial dysplasia in humans and mice, a syndrome characterized by generalized bone defects. Lastly, Cbfa1 was shown to have a role beyond development and differentiation, regulating the rate of bone matrix deposition by differentiated osteoblasts. Thus, Cbfa1 is a critical gene not only for osteoblast differentiation but also for osteoblast function. These aspects, as well as the more recent progresses in understanding Cbfa1 biology, are the focuses of this review. (+info)