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Stefan Mundlos - One of the best experts on this subject based on the ideXlab platform.

  • Cleidocranial Dysplasia with decreased bone density and biochemical findings of hypophosphatasia
    European Journal of Pediatrics, 2002
    Co-Authors: Eva Morava, Stefan Mundlos, Judit Karteszi, Janos Weisenbach, Almuth Caliebe, K Mehes
    Abstract:

    Cleidocranial Dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal Dysplasia characterised by hypoplastic clavicles, patent fontanelles, short stature, tooth anomalies and other variable skeletal changes. Different mutations of the RUNX2/CBFA1 gene (MIM 600211) have been detected in patients with CCD. We investigated a mother and daughter with features of CCD presenting with reduced plasma alkaline phosphatase activity, increased urinary phosphoethanolamine excretion and decreased bone density. The latter findings were suggestive of hypophophatasia but mutation analysis showed no mutation in the tissue-nonspecific alkaline phosphatase gene (TNSALP; MIM 171760). However, a heterozygous mutation (Arg169Pro caused by nucleotide change 506G>C) was detected in the RUNX2 gene. Metabolic alterations gradually improved in both mother and daughter but bone-specific alkaline phosphatase remained low (less than 30% of normal) and mild phosphoethanolaminuria persisted. Recent studies in the Cbfa1 knock-out mouse showed decreased expression of alkaline phosphatase in differentiating bone. Conclusion: we suggest that the observed metabolic alterations are secondary to the RUNX2 gene mutation affecting early bone maturation and turnover. This is the first description of biochemical findings of hypophosphatasia in patients with Cleidocranial Dysplasia.

  • severe Cleidocranial Dysplasia can mimic hypophosphatasia
    European Journal of Pediatrics, 2002
    Co-Authors: Sheila Unger, Stefan Mundlos, Etienne Mornet, Susan Blaser, David E C Cole
    Abstract:

    Cleidocranial Dysplasia (OMIM 119600) is a skeletal Dysplasia caused by mutations in the bone/cartilage specific osteoblast transcription factor RUNX2 gene. It is characterised by macrocephaly with persistently open sutures, absent or hypoplastic clavicles, dental anomalies, and delayed ossification of the pubic bones. A few patients have been reported with recurrent fractures or osteoporosis but these are not considered features of the disease. We report a patient with classical findings of Cleidocranial Dysplasia: markedly hypoplastic clavicles, delayed ossification of the pubic rami, multiple pseudoepiphyses of the metacarpals, and dental anomalies including delayed eruption of permanent dentition and multiple supernumerary teeth. The patient also had radiographic and biochemical features of hypophosphatasia (OMIM 241500, 146300) and was initially diagnosed with this condition. Serum alkaline phosphatase activity has been consistently reduced and specific enzyme substrates, phosphoethanolamine and pyridoxal-5'-phosphate, have been elevated. However, no mutations were found on direct sequencing of the tissue-nonspecific alkaline phosphatase (TNSALP) gene using a protocol that detects up to 94% of all mutations causing hypophosphatasia. Conclusion: We propose that a subset of patients with Cleidocranial Dysplasia have features of secondary hypophosphatasia due to decreased expression of the tissue-nonspecific alkaline phosphatase gene.

  • mutations in the runx2 gene in patients with Cleidocranial Dysplasia
    Human Mutation, 2002
    Co-Authors: Florian Otto, Hirokazu Kanegane, Stefan Mundlos
    Abstract:

    Cleidocranial Dysplasia (CCD) is a autosomal dominant disorder characterized by skeletal anomalies such as patent fontanels, late closure of cranial sutures with Wormian bones, late erupting secondary dentition, rudimentary clavicles, and short stature. The locus for this disease was mapped to chromosome 6p21. RUNX2 is a member of the runt family of transcription factors and its expression is restricted to developing osteoblasts and a subset of chondrocytes. Mutations in the RUNX2 gene have been shown to cause CCD. Chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, as well as missense mutations of the RUNX2 gene have been described in CCD patients. Although there is a wide spectrum in phenotypic variability ranging from primary dental anomalies to all CCD features plus osteoporosis, no clear phenotype–genotype correlation has been established. However analysis of the three-dimensional structure of the DNA binding runt domain of the RUNX proteins and its interaction with DNA, as well as the cofactor CBFB, start to provide an insight into how missense mutations affect RUNX2 function. Hum Mutat 19:209–216, 2002. © 2002 Wiley-Liss, Inc.

  • Mutations in the RUNX2 gene in patients with Cleidocranial Dysplasia.
    Human Mutation, 2002
    Co-Authors: Florian Otto, Hirokazu Kanegane, Stefan Mundlos
    Abstract:

    Cleidocranial Dysplasia (CCD) is a autosomal dominant disorder characterized by skeletal anomalies such as patent fontanels, late closure of cranial sutures with Wormian bones, late erupting secondary dentition, rudimentary clavicles, and short stature. The locus for this disease was mapped to chromosome 6p21. RUNX2 is a member of the runt family of transcription factors and its expression is restricted to developing osteoblasts and a subset of chondrocytes. Mutations in the RUNX2 gene have been shown to cause CCD. Chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, as well as missense mutations of the RUNX2 gene have been described in CCD patients. Although there is a wide spectrum in phenotypic variability ranging from primary dental anomalies to all CCD features plus osteoporosis, no clear phenotype-genotype correlation has been established. However analysis of the three-dimensional structure of the DNA binding runt domain of the RUNX proteins and its interaction with DNA, as well as the cofactor CBFB, start to provide an insight into how missense mutations affect RUNX2 function.

  • Cleidocranial Dysplasia clinical and molecular genetics
    Journal of Medical Genetics, 1999
    Co-Authors: Stefan Mundlos
    Abstract:

    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.

Florian Otto - One of the best experts on this subject based on the ideXlab platform.

  • mutations in the runx2 gene in patients with Cleidocranial Dysplasia
    Human Mutation, 2002
    Co-Authors: Florian Otto, Hirokazu Kanegane, Stefan Mundlos
    Abstract:

    Cleidocranial Dysplasia (CCD) is a autosomal dominant disorder characterized by skeletal anomalies such as patent fontanels, late closure of cranial sutures with Wormian bones, late erupting secondary dentition, rudimentary clavicles, and short stature. The locus for this disease was mapped to chromosome 6p21. RUNX2 is a member of the runt family of transcription factors and its expression is restricted to developing osteoblasts and a subset of chondrocytes. Mutations in the RUNX2 gene have been shown to cause CCD. Chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, as well as missense mutations of the RUNX2 gene have been described in CCD patients. Although there is a wide spectrum in phenotypic variability ranging from primary dental anomalies to all CCD features plus osteoporosis, no clear phenotype–genotype correlation has been established. However analysis of the three-dimensional structure of the DNA binding runt domain of the RUNX proteins and its interaction with DNA, as well as the cofactor CBFB, start to provide an insight into how missense mutations affect RUNX2 function. Hum Mutat 19:209–216, 2002. © 2002 Wiley-Liss, Inc.

  • Mutations in the RUNX2 gene in patients with Cleidocranial Dysplasia.
    Human Mutation, 2002
    Co-Authors: Florian Otto, Hirokazu Kanegane, Stefan Mundlos
    Abstract:

    Cleidocranial Dysplasia (CCD) is a autosomal dominant disorder characterized by skeletal anomalies such as patent fontanels, late closure of cranial sutures with Wormian bones, late erupting secondary dentition, rudimentary clavicles, and short stature. The locus for this disease was mapped to chromosome 6p21. RUNX2 is a member of the runt family of transcription factors and its expression is restricted to developing osteoblasts and a subset of chondrocytes. Mutations in the RUNX2 gene have been shown to cause CCD. Chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, as well as missense mutations of the RUNX2 gene have been described in CCD patients. Although there is a wide spectrum in phenotypic variability ranging from primary dental anomalies to all CCD features plus osteoporosis, no clear phenotype-genotype correlation has been established. However analysis of the three-dimensional structure of the DNA binding runt domain of the RUNX proteins and its interaction with DNA, as well as the cofactor CBFB, start to provide an insight into how missense mutations affect RUNX2 function.

  • mutations involving the transcription factor cbfa1 cause Cleidocranial Dysplasia
    Cell, 1997
    Co-Authors: Florian Otto, Stefan Mundlos, C Mundlos, John B Mulliken, Arthur S Aylsworth, S Albright, D Lindhout, W G Cole
    Abstract:

    Cleidocranial Dysplasia (CCD) is an autosomal-dominant condition characterized by hypoplasia/aplasia of clavicles, patent fontanelles, supernumerary teeth, short stature, and other changes in skeletal patterning and growth. In some families, the phenotype segregates with deletions resulting in heterozygous loss of CBFA1, a member of the runt family of transcription factors. In other families, insertion, deletion, and missense mutations lead to translational stop codons in the DNA binding domain or in the C-terminal transactivating region. In-frame expansion of a polyalanine stretch segregates in an affected family with brachydactyly and minor clinical findings of CCD. We conclude that CBFA1 mutations cause CCD and that heterozygous loss of function is sufficient to produce the disorder.

Sven Kreiborg - One of the best experts on this subject based on the ideXlab platform.

  • tooth formation and eruption lessons learnt from Cleidocranial Dysplasia
    European Journal of Oral Sciences, 2018
    Co-Authors: Sven Kreiborg, Birgit Jensen
    Abstract:

    The principles of formation, renewal, and eruption of teeth are discussed. Numerous genetic aberrations may affect the formation and eruption of teeth. Cleidocranial Dysplasia (CCD), caused by mutations in the runt-related transcription factor 2 (RUNX2) gene, is such a condition. The dental phenotype includes problems in both tooth formation (multiple supernumerary permanent teeth) and tooth eruption (lack of shedding of primary teeth and delayed or arrested eruption of permanent teeth). Clinical studies, animal models, and molecular biology studies have documented that RUNX2 is of paramount importance for osteoblast differentiation, for regression of the dental lamina, and for osteoclastogenesis in the dental follicle and the periodontal ligament. Jensen & Kreiborg, 25 yr ago, proposed a treatment strategy to be applied to patients with CCD, focussing on the importance of early treatment to promote spontaneous eruption of permanent teeth through extraction of primary teeth, surgical removal of supernumerary teeth, and removal of bone covering the first formed permanent teeth at the time when root formation of the permanent teeth has reached half or two-thirds of their final length. This strategy still seems valid and seems to lead to reduction in the burden of care for patients compared with the treatment protocols otherwise recommended.

  • runx2 analysis of danish Cleidocranial Dysplasia families
    Clinical Genetics, 2011
    Co-Authors: Lars J Hansen, A K Riis, Asli Silahtaroglu, Hanne B Hove, Eva Lauridsen, Hans Eiberg, Sven Kreiborg
    Abstract:

    Cleidocranial Dysplasia (CCD) is an autosomal dominant inherited disease caused by mutations in the Runt gene RUNX2. Screening of 19 Danish CCD families revealed 16 pathogenic mutations (84%) representing 8 missense mutations, 2 nonsense mutations, 4 frame-shift mutations and 2 large deletions in the RUNX2 locus. Eight mutations were novel, two were found twice, and polymorphisms were found in the promoter region and in the conserved polyglutamine/polyalanine repeat. A large duplication downstream of RUNX2 found in one patient suggests a possible regulatory RUNX2 element. The CCD phenotypes and genotypes adhere to the large phenotypic variability reported in previous CCD studies. Identification of large chromosome aberrations in or near the RUNX2 locus in 3 of the 19 cases suggests copy number analyses to be included in future RUNX2 mutation analyses.

  • anomalies of craniofacial skeleton and teeth in Cleidocranial Dysplasia
    Journal of Craniofacial Genetics and Developmental Biology, 1999
    Co-Authors: Sven Kreiborg, Birgit Jensen, Per Larsen, D T Schleidt, Tron A Darvann
    Abstract:

    Mutations involving the transcription factor CBFA1 cause Cleidocranial Dysplasia (CCD) in man. Recently, a mouse model of CCD has been generated (Cbfal +/-) [Komori et al., 1997], and disturbances of osteoclast differentiation have been documented. It has been shown that these animals exhibit hypoplastic clavicles and nasal bones, and retarded ossification of parietal, interparietal, and supraoccipital bones. Humans with CCD show all these features, including severely retarded ossification of the cranial base, strongly suggesting that both intramembranous ossification and endochondral ossification are affected. In addition, CCD patients have multiple supernumerary teeth and delayed tooth eruption. The present report presents 3D reconstructions of computerised tomography (CT) scans of the craniofacial region of a CCD boy examined at both 1 and 7 years of age. The anomalies in craniofacial skeleton and teeth are analysed and compared to the findings of our previous clinical studies and to the findings in the animal model. Based on the available information, we suggest that osteoblast, osteoclast, and dentinoclast differentiation may be disturbed in CCD.

  • craniofacial growth in Cleidocranial Dysplasia a roentgencephalometric study
    Journal of Craniofacial Genetics and Developmental Biology, 1995
    Co-Authors: B L Jensen, Sven Kreiborg
    Abstract:

    The purpose of this study was to analyze craniofacial growth in Cleidocranial Dysplasia (CCD) with emphasis on bone remodeling, mandibular condylar growth, and tooth eruption. Skull radiographs of 22 CCD children followed longitudinally were examined. The span of time investigated varied for each patient, but the period from 5 years to adult age was well covered. Five patients had metallic implants inserted in the jaws; the implants enabled detailed analysis of bone remodeling, jaw rotation, and tooth eruption. In the calvaria, an open anterior fontanelle area persisted in most cases but decreased with age. A frontal sinus failed to develop or was diminutive in all cases but one. In the cranial base, the size increase of the sella turcica was reduced as a result of modest resorption at the floor and the posterior wall; the clivus was flexed in most cases, but the flexion remained stable during the observation period. Growth in maxillary height was severely reduced, primarily because resorptive lowering of the nasal floor was minimal. The amount of bone apposition on the orbital floor and the alveolar process was smaller than expected. Condylar growth direction was vertical giving rise to a forward rotation of the mandible in relation to the anterior cranial base. The expected resorptive remodeling below the mandibular angle and anteriorly on the ramus was negligible. The low maxilla, in combination with a marked forward mandibular rotation in cases with unstable occlusion as a consequence of eruption problems in the permanent dentition, gave rise to a diminished anterior facial height.(ABSTRACT TRUNCATED AT 250 WORDS)

  • development of the dentition in Cleidocranial Dysplasia
    Tandlaegebladet, 1991
    Co-Authors: Birgit Jensen, Sven Kreiborg
    Abstract:

    The purpose of the present investigation was to describe the formation, maturation and eruption of the dentition, including supernumerary teeth in a sample of patients with Cleidocranial Dysplasia. The dentition was evaluated from orthopantomograms, intraoral radiographs, cephalometric films, surgically removed teeth and intraoral photographs in 22 patients (10 men, 12 women), aged 3.5 to 34 years. Formation of primary teeth was normal, whereas all patients but one had supernumerary permanent teeth. Frequency of supernumerary teeth ranged from 22% in the maxillary incisor region to 5% in the molar regions. Anterior to the molar region supernumerary teeth were formed lingually and occlusally to the normal teeth. Maturation of the primary dentition was normal, while permanent teeth were delayed from 1 to 4 years. Supernumerary teeth were delayed about 4 years in relation to normal permanent teeth. Eruption of primary teeth was normal, whereas all patients had severe eruption problems of permanent teeth.(ABSTRACT TRUNCATED AT 250 WORDS)

Yoshiaki Ito - One of the best experts on this subject based on the ideXlab platform.

Yuwen Zhang - One of the best experts on this subject based on the ideXlab platform.

  • a runx2 pebp2αa cbfa1 mutation displaying impaired transactivation and smad interaction in Cleidocranial Dysplasia
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Yuwen Zhang, Natsuo Yasui, Takahiro Ochi, Kosei Ito, Gang Huang, Makiko Fujii, Junichi Hanai, Hiroshi Nogami, Kohei Miyazono, Yoshiaki Ito
    Abstract:

    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 2αA (PEBP2αA)/core-binding factor A1 (CBFA1). To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, CCDαA376, 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 β 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 β/bone morphogenetic protein pathways that target the activity of RUNX2 during bone formation.

  • pebp2αa cbfa1 mutations in japanese Cleidocranial Dysplasia patients
    Gene, 2000
    Co-Authors: Yuwen Zhang, Natsuo Yasui, Naoki Kakazu, Tatsuo Abe, Kenzo Takada, Shosuke Imai, Motohiko Sato, Shintaro Nomura, Takahiro Ochi, Shigeharu Okuzumi
    Abstract:

    Cleidocranial Dysplasia (CCD) is an autosomal dominant human bone disease whose genetic locus has been located on chromosome 6p21, where the PEBP2alphaA/CBFA1 gene essential for osteogenesis also maps. Previously, several heterozygous mutations in PEBP2alphaA/CBFA1 were found in CCD patients. In this study, we identified six different types of mutations in PEBP2alphaA/CBFA1 in Japanese CCD patients. Four cases were similar to those reported previously: two were nonsense mutations in the Runt domain, one was a hemizygous deletion, and the other was a missense mutation in the Runt domain which abolished the DNA-binding activity of Runx2/PEBP2alphaA/CBFA1. The remaining two mutations were novel: one had a heterozygous gt-to-tt mutation at the splice donor site (gt) between the exon3-intron junction, which resulted in abnormal exon3 skipping, and the other had a mutation in exon7, which led to the introduction of a translational stop codon in the middle of the transactivation domain. Thus, defects in either the DNA-binding domain or transactivation domain of Runx2/PEBP2alphaA/CBFA1 can cause CCD. The results not only provide a strong genetic evidence that mutations involving in PEBP2alphaA/CBFA1 contribute to CCD, but also provide a useful tool to study how Runx2/PEBP2alphaA/CBFA1 plays its pivotal role during osteoblastic differentiation.

  • the cdna cloning of the transcripts of human pebp2αa cbfa1 mapped to 6p12 3 p21 1 the locus for Cleidocranial Dysplasia
    Oncogene, 1997
    Co-Authors: Yuwen Zhang, Sukchul Bae, Eiichi Takahashi, Yoshiaki Ito
    Abstract:

    The cDNA cloning of the transcripts of human PEBP2αA/CBFA1 mapped to 6p12.3-p21.1, the locus for Cleidocranial Dysplasia