Genetic mapping of the Camurati-Engelmann disease locus to chromosome 19q13.1-q13.3. (1/24)

Camurati-Engelmann disease (CED [MIM 131300]), or progressive diaphyseal dysplasia, is an autosomal dominant sclerosing bone dysplasia characterized by progressive bone formation along the periosteal and endosteal surfaces at the diaphyseal and metaphyseal regions of long bones and cranial hyperostosis, particularly at the skull base. The gene for CED, or its chromosomal localization, has not yet been identified. We performed a genomewide linkage analysis of two unrelated Japanese families with CED, in which a total of 27 members were available for this study; 16 of them were affected with the disease. Two-point linkage analysis revealed a maximum LOD score of 7.41 (recombination fraction.00; penetrance 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at chromosome 19q13.1-q13.3. These findings, together with a genetic distance among the marker loci, indicate that the CED locus can be assigned to a 15.1-cM segment between D19S881 and D19S606.  (+info)

Localisation of the gene causing diaphyseal dysplasia Camurati-Engelmann to chromosome 19q13. (2/24)

Camurati-Engelmann disease, progressive diaphyseal dysplasia, or diaphyseal dysplasia Camurati-Engelmann is a rare, autosomal dominantly inherited bone disease, characterised by progressive cortical expansion and sclerosis mainly affecting the diaphyses of the long bones associated with cranial hyperostosis. The main clinical features are severe pain in the legs, muscular weakness, and a waddling gait. The underlying cause of this condition remains unknown. In order to localise the disease causing gene, we performed a linkage study in a large Jewish-Iraqi family with 18 affected subjects in four generations. A genome wide search with highly polymorphic markers showed linkage with several markers at chromosome 19q13. A maximum lod score of 4.9 (theta=0) was obtained with markers D19S425 (58.7 cM, 19q13.1) and D19S900 (67.1 cM, 19q13. 2). The disease causing gene is located in a candidate region of approximately 32 cM, flanked by markers D19S868 (55.9 cM, 19q13.1) and D19S571 (87.7 cM, 19q13.4).  (+info)

Domain-specific mutations of a transforming growth factor (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1. (3/24)

Transforming growth factor (TGF)-beta1 is secreted as a latent form, which consists of its mature form and a latency-associated peptide (beta1-LAP) in either the presence or the absence of additional latent TGF-beta1-binding protein. We recently reported that three different missense mutations (R218H, R218C, and C225R) of beta1-LAP cause the Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by hyperosteosis and sclerosis of the diaphysis of the long bones. Pulse-chase experiments using fibroblasts from CED patients and expression experiments of the mutant genes in an insect cell system suggest that these mutations disrupt the association of beta1-LAP and TGF-beta1 and the subsequent release of the mature TGF-beta1. Furthermore, the cell growth of fibroblasts from a CED patient and mutant gene-transfected fibroblasts was suppressed via TGF-beta1. The growth suppression observed was attenuated by neutralizing antibody to TGF-beta1 or by treatment of dexamethasone. On the other hand, the proliferation of human osteoblastic MG-63 cells was accelerated by coculture with CED fibroblasts. These data suggest that the domain-specific mutations of beta1-LAP result in a more facile activation of TGF-beta1, thus causing CED.  (+info)

Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. (4/24)

Transforming growth factor-beta1 (TGF-beta1) is secreted as a latent precursor, consisting of a homodimer of the latency-associated peptide and the mature peptide. TGFbeta-1 can only exert its many functions after going from this latent to an active state, in which the binding site of the mature peptide for its receptor is no longer shielded by the latency-associated peptide. We and others reported that mutations in TGFB1 cause Camurati-Engelmann disease, a rare bone disorder. Until now, seven mutations have been published. In this study, we investigate the effect of the LLL12-13ins, Y81H, R218C, H222D, and C225R mutations on the functioning of TGF-beta1 in vitro. A luciferase reporter assay specific for TGF-beta-induced transcriptional response with wild type and mutant TGF-beta1 constructs showed a positive effect of all mutations on TGF-beta1 activity. By way of enzyme-linked immunosorbent assay, we found that in the R218C, H222D, and C225R mutant constructs, this effect is caused by an increase in active TGF-beta1 in the medium of transfected cells. The LLL12-13ins and Y81H mutations on the contrary have a profound effect on secretion; a decreased amount of TGF-beta1 is secreted, but the increased luciferase activity shows that the intracellular accumulation of (aberrant) TGF-beta1 can initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-beta1 signaling, thus causing Camurati-Engelmann disease.  (+info)

Camurati-Engelmann's disease: a case report. (5/24)

Camurati-Engelmann's disease is a rare condition worldwide. No cases have been documented in Uganda. A 26 year old female presented with a history of grinding pain in the limbs for over 20 years. Strong painkillers would temporally relieve the pain. She had an asthenic stature with generalised reduction in muscle bulk. Plain x-rays revealed the characteristic symmetrical thickening and sclerosis of the diaphyses of the appendicular skeleton and skull base, which is pathognomonic of Camurati-Engelmann's disease. Involvement of the metaphyses of these long bones as well as the metacarpal bones makes this an unusual case.  (+info)

The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD). (6/24)

Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.  (+info)

Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment. (7/24)

Camurati-Engelmann disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) beta1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.  (+info)

Rare osteodysplasia of the temporal bone. (8/24)

Temporal bone osteodysplasia can produce many different symptoms, such as involvement restricted to the temporal bone or impairment of other bones. We consider, in this study two entities that are rare osteodysplasia cases, which are osteopetrosis and Camurati-Engelmann disease, the latter being extremely rare. We present two cases of benign form of osteopetrosis (Albers-Schulenburg's disease), a patient of 11 years old and another one of 48 years old, both male, and a patient of 28 years old, female, with Camurati-Engelmann's disease. The facial palsy was a manifestation in two of the patients. We discuss some aspects about the clinical manifestations, radiological findings, as well as differential diagnostic and therapy in view of the complications of the diseases.  (+info)

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