Mutations AIP chez les jeunes patients en-dessous de 30 ans avec adénome hypophysaire agressif

in 27ème Congrès de la Société Française d'Endocrinologie - Deauville, 29 septembre - 2 octobre 2010 (2010, September)

Mutations des localisations des services et mutations urbaines. Questionnements et perspectives

in Revista de Geografia, Universidade Federal de Pernambuco (2002), 17(2), 41-56

The aim of this paper is to analyse the relationships between urban mutations and service locations. Work is developed in four times: facts, causes, consequences and prospects. Without doubt, the spatial ... [more ▼]

The aim of this paper is to analyse the relationships between urban mutations and service locations. Work is developed in four times: facts, causes, consequences and prospects. Without doubt, the spatial transfers of service activities can be considered as both, a cause and a consequence of urban sprawl. It is related to the release of mobility constraints, to the specific changes that affected many economic activities, and also to the new behaviours of many actors (customers/ visitors, property developers and public authorities). As this evolution is incompatible with the objectives of sustainable urban development, several action possibilities can be proposed: new management of the daily mobilities, reduction in space consumption and new governance. [less ▲]

Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome.

in Journal of Bone and Mineral Research (2011)

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and post-translational modification of type I collagen. Autosomal ... [more ▼]

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and post-translational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, while Bruck Syndrome type 1 has been mapped to 17q12 but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique post-translational modification of type I procollagen, i.e. 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB) form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), has also been shown to be mutated in recessive OI. Here, we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Given the previous mapping of Bruck syndrome type 1 to the chromosomal region containing FKBP10, we conclude that FKBP10 mutations are the cause of Bruck syndrome type 1. (c) 2010 American Society for Bone and Mineral Research. [less ▲]

Mutations in PYCR1 cause cutis laxa with progeroid features.

in Nature Genetics (2009), 41(9), 1016-21

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity ... [more ▼]

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues. [less ▲]

Mutations In The Bovine Leukemia-Virus Tax Protein Can Abrogate The Long Terminal Repeat-Directed Transactivating Activity Without Concomitant Loss Of Transforming Potential

in Proceedings of the National Academy of Sciences of the United States of America (1992), 89(9),

Mutations in the inositol polyphosphate-5-phosphatase E gene link phosphatidyl inositol signaling to the ciliopathies

in Nature Genetics (2009), 41

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1 ... [more ▼]

Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events1. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation (‘molar tooth sign’), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly2 and is included in the newly emerging group of ‘ciliopathies’. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function [less ▲]

Mutations in type 1 procollagen that cause osteogenesis imperfecta: effects of the mutations on the assembly of collagen into fibrils, the basis of phenotypic variations, and potential antisense therapies.

in Journal of Bone and Mineral Research (1993), 8 Suppl 2

Work by a large number of investigators over the last decade has established that over 90% of patients with osteogenesis imperfecta have mutations in one of the two genes for type I procollagen, that most ... [more ▼]

Work by a large number of investigators over the last decade has established that over 90% of patients with osteogenesis imperfecta have mutations in one of the two genes for type I procollagen, that most unrelated probands have different mutations in the genes, and that the mutations found in most of the serious variants of the disease cause synthesis of abnormal pro alpha chains of the protein. The results have demonstrated that synthesis of structurally abnormal but partially functional pro alpha chains can interfere with folding of the central region of the protein into a triple-helical conformation, prevent processing of the N-terminal propeptides of procollagen, or produce subtle alterations in conformation that interfere with the self-assembly of the protein into collagen fibrils. One of the unsolved mysteries about the disease is why some mutations produce severe phenotypes, whereas very similar mutations produce mild phenotypes. Recent studies in transgenic mice suggest that nongenetic factors, such as stochastic events during development, may determine the severity of the disease phenotype produced by a specific mutation. Also, recent results raised the possibility that strategies of antisense gene therapy may be effective in treating the disease some time in the future. Specific inhibition of expression of a mutated collagen gene has been obtained with antisense oligonucleotides in cell culture experiments. However, there is no means of selective delivery of antisense oligonucleotides to the appropriate tissues. [less ▲]

Mutations near amino end of alpha 1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing

in Journal of Biological Chemistry (2005), 280(19), 19259-19269

Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children ... [more ▼]

Patients with OI/EDS form a distinct subset of osteogenesis imperfecta (OI) patients. In addition to skeletal fragility, they have characteristics of Ehlers-Danlos syndrome (EDS). We identified 7 children with types III or IV OI, plus severe large and small joint laxity and early progressive scoliosis. In each child with OI/EDS, we identified a mutation in the first 90 residues of the helical region of α 1(I) collagen. These mutations prevent or delay removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS-2) in vitro and in pericellular assays. The mutant pN-collagen which results is efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and is prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils have significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. Differential scanning calorimetry revealed that these mutant collagens are less stable than the corresponding procollagens, which is not seen with other type I collagen helical mutations. These mutations disrupt a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and alter the secondary structure of the adjacent N-proteinase cleavage site. Thus, these OI/EDS collagen mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal. [less ▲]

Mutations of calcium-sensing receptor gene: two novel mutations and overview of impact on calcium homeostasis

in European Journal of Endocrinology (2011)

Objective: Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis and study of the CASR ... [more ▼]

Objective: Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis and study of the CASR gene can be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novel CASR gene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CaSR function. Patients and Methods: A 16 yr-old patient had mild hypercalcemia associated with low-normal urinary calcium excretion and normal-to-high parathyroid hormone (PTH) levels. Because of negative family history, familial hypocalciuric hypercalcemia (FHH) was originally excluded. The second patient was a 54 yr-old man with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild hypercalciuria. Familial investigation revealed the same phenotype in the patient's sister. The coding region of the CaSR gene was sequenced in both probands and their available first-degree relatives. Results: The first patient had a novel heterozygous inactivating CASR mutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activating CASR mutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive. Conclusions: We reported two novel heterozygous mutations of the CASR gene, an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6. These cases illustrate the importance of genetic testing of CASR gene to aid correct diagnosis and to assist in clinical management. [less ▲]

Mutations récentes de la structure et de la localisation de l'industrie en Belgique, 1970-1980

in Hommes et Terres du Nord (1980), (4), 41-51

The aim of this article is to distinguish the principal changes which have affected Belgian industry since 1970 - changes in structure, on one hand, and in localisation, on the other. When examining the ... [more ▼]

The aim of this article is to distinguish the principal changes which have affected Belgian industry since 1970 - changes in structure, on one hand, and in localisation, on the other. When examining the available data, four main facts seem to emerge : the distinct fall in employment in most branches, the difficulties in maintaining the fields most threatened by foreign competition, the problems in developing regions where declining industries are concentrated and the very dear impact of industrial zones in new localisations. [less ▲]