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861.
Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease 总被引:16,自引:0,他引:16
Sakuntabhai A Ruiz-Perez V Carter S Jacobsen N Burge S Monk S Smith M Munro CS O'Donovan M Craddock N Kucherlapati R Rees JL Owen M Lathrop GM Monaco AP Strachan T Hovnanian A 《Nature genetics》1999,21(3):271-277
Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis. 相似文献
862.
863.
864.
Genomic instability in Gadd45a-deficient mice. 总被引:19,自引:0,他引:19
M C Hollander M S Sheikh D V Bulavin K Lundgren L Augeri-Henmueller R Shehee T A Molinaro K E Kim E Tolosa J D Ashwell M P Rosenberg Q Zhan P M Fernández-Salguero W F Morgan C X Deng A J Fornace 《Nature genetics》1999,23(2):176-184
Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability. 相似文献
865.
866.
867.
CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. 总被引:3,自引:0,他引:3
J Marcelino J D Carpten W M Suwairi O M Gutierrez S Schwartz C Robbins R Sood I Makalowska A Baxevanis B Johnstone R M Laxer L Zemel C A Kim J K Herd J Ihle C Williams M Johnson V Raman L G Alonso D Brunoni A Gerstein N Papadopoulos S A Bahabri J M Trent M L Warman 《Nature genetics》1999,23(3):319-322
Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities. 相似文献
868.
Laping NJ 《Cellular and molecular life sciences : CMLS》1999,56(5-6):371-377
Hepatocyte growth factor (HGF) is an injury-released growth factor with diverse effects on epithelial and endothelial cells. These effects include proliferation, migration, extracellular matrix production and tubulogenesis. These activities allow HGF to function as an organizer of repair processes that bring about restoration of tubular function following renal injury. However, while HGF has been demonstrated to accelerate recovery of renal function after an acute insult, prolonged exposure to elevated levels of HGF can reduce renal function and may contribute to progressive renal disease. This review will describe the cellular activities of HGF, how they pertain to renal repair and the therapeutic application of regulating HGF activity in acute versus chronic renal disease. 相似文献
869.
A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor 总被引:14,自引:0,他引:14
Madsen LS Andersson EC Jansson L krogsgaard M Andersen CB Engberg J Strominger JL Svejgaard A Hjorth JP Holmdahl R Wucherpfennig KW Fugger L 《Nature genetics》1999,23(3):343-347
Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development less compared with their contribution to disorders such as insulin-dependent diabetes mellitus. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 4102 peptide; and the human CD4 coreceptor. The amino acid sequence of the MBP 84-102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells. 相似文献
870.
Hazan J Fonknechten N Mavel D Paternotte C Samson D Artiguenave F Davoine CS Cruaud C Dürr A Wincker P Brottier P Cattolico L Barbe V Burgunder JM Prud'homme JF Brice A Fontaine B Heilig B Weissenbach J 《Nature genetics》1999,23(3):296-303
Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes. 相似文献