calcium binding proteins


Summary: Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS.

Top Publications

  1. Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit V, Monack D. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med. 2010;207:1745-55 pubmed publisher
    ..typhimurium, mice lacking both NLRs were markedly more susceptible to infection. These results reveal unexpected redundancy among NLRs in host defense against intracellular pathogens in vivo. ..
  2. Vergarajauregui S, Martina J, Puertollano R. Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1. J Biol Chem. 2009;284:36357-66 pubmed publisher
    ..Overall, our data provide new insight into the molecular mechanisms that regulate MCOLN1 activity. We propose that ALG-2 acts as a Ca(2+) sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway...
  3. Hewitt L, Tighe A, Santaguida S, White A, Jones C, Musacchio A, et al. Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. J Cell Biol. 2010;190:25-34 pubmed publisher
    ..We propose a model whereby Mps1 transphosphorylation results in its release from kinetochores, thus facilitating recruitment of O-Mad2 and CENP-E and thereby simultaneously promoting checkpoint signaling and chromosome congression. ..
  4. Miao E, Warren S. Innate immune detection of bacterial virulence factors via the NLRC4 inflammasome. J Clin Immunol. 2010;30:502-6 pubmed publisher
    ..Both flagellin and rod protein are unintentionally delivered to the mammalian cytosol by the bacterium through the T3SS. ..
  5. Miao E, Mao D, YUDKOVSKY N, Bonneau R, Lorang C, Warren S, et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A. 2010;107:3076-80 pubmed publisher
    ..Furthermore, the specific detection of the virulence machinery permits the discrimination between pathogenic and nonpathogenic bacteria. ..
  6. Warren S, Armstrong A, Hamilton M, Mao D, Leaf I, Miao E, et al. Cutting edge: Cytosolic bacterial DNA activates the inflammasome via Aim2. J Immunol. 2010;185:818-21 pubmed publisher
    ..We now use biochemical and genetic approaches to demonstrate that the third detector senses bacterial DNA and identify it as Aim2, a receptor that has previously been shown to detect viral DNA. ..
  7. Tsuchiya K, Hara H, Kawamura I, Nomura T, Yamamoto T, Daim S, et al. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J Immunol. 2010;185:1186-95 pubmed publisher
    ..monocytogenes-infected macrophages. These results suggest that AIM2, in cooperation with NLRP3 and NLRC4, plays an important role in the activation of caspase-1 during L. monocytogenes infection. ..
  8. Dason J, Romero Pozuelo J, Marin L, Iyengar B, Klose M, Ferrús A, et al. Frequenin/NCS-1 and the Ca2+-channel alpha1-subunit co-regulate synaptic transmission and nerve-terminal growth. J Cell Sci. 2009;122:4109-21 pubmed publisher
    ..Overall, Frq modulates Ca(2+) entry through a functional interaction with the alpha(1) voltage-gated Ca(2+)-channel subunit; this interaction regulates neurotransmission and nerve-terminal growth. ..
  9. Janssen A, Kops G, Medema R. Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc Natl Acad Sci U S A. 2009;106:19108-13 pubmed publisher
    ..Thus, targeting the mitotic checkpoint and chromosome alignment simultaneously may selectively kill tumor cells by enhancing chromosome mis-segregations. ..

More Information


  1. Yoon K, Cho J, Lee J, Kang Y, Chae J, Kim Y, et al. CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1. Proc Natl Acad Sci U S A. 2009;106:17389-94 pubmed publisher
    ..These observations thus suggest that CIB1 functions as a Ca(2+)-sensitive negative regulator of ASK1-mediated signaling events. ..
  2. Jiang D, Zhao L, Clapham D. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science. 2009;326:144-7 pubmed publisher
    ..RNAi knockdown, overexpression, and liposome reconstitution of the purified Letm1 protein demonstrate that Letm1 is a mitochondrial Ca2+/H+ antiporter. ..
  3. Sahu S, Aradhyam G, Gummadi S. Calcium binding studies of peptides of human phospholipid scramblases 1 to 4 suggest that scramblases are new class of calcium binding proteins in the cell. Biochim Biophys Acta. 2009;1790:1274-81 pubmed publisher
    ..Our findings will be relevant in understanding the calcium dependent scrambling activity of hPLSCRs and their biological function. ..
  4. Shio M, Tiemi Shio M, Eisenbarth S, Savaria M, Vinet A, Bellemare M, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 2009;5:e1000559 pubmed publisher
    ..These findings not only identify one way by which the immune system is alerted to malarial infection but also are one of the first to suggest a role for tyrosine kinase signaling pathways in regulation of the NLRP3 inflammasome. ..
  5. Yang Z, Kenny A, Brito D, Rieder C. Cells satisfy the mitotic checkpoint in Taxol, and do so faster in concentrations that stabilize syntelic attachments. J Cell Biol. 2009;186:675-84 pubmed publisher
    ..They also offer an explanation for why some cells are more sensitive to lower versus higher Taxol concentrations. ..
  6. Okamoto M, Matsuda H, Joetham A, Lucas J, Domenico J, Yasutomo K, et al. Jagged1 on dendritic cells and Notch on CD4+ T cells initiate lung allergic responsiveness by inducing IL-4 production. J Immunol. 2009;183:2995-3003 pubmed publisher
    ..These data identify the essential role of the interactions between Notch on CD4(+) T cells and Jagged1 on APCs in the initiation of IL-4 production and Th2 differentiation for the development of AHR and allergic airway inflammation. ..
  7. Royer L, Sztretye M, Manno C, Pouvreau S, Zhou J, Knollmann B, et al. Paradoxical buffering of calcium by calsequestrin demonstrated for the calcium store of skeletal muscle. J Gen Physiol. 2010;136:325-38 pubmed publisher
    ..The study revealed a surprisingly modest loss of Ca(2+) storage capacity in null cells, which may reflect concurrent changes, rather than detract from the physiological importance of calsequestrin...
  8. Dehne T, Schenk R, Perka C, Morawietz L, Pruss A, Sittinger M, et al. Gene expression profiling of primary human articular chondrocytes in high-density micromasses reveals patterns of recovery, maintenance, re- and dedifferentiation. Gene. 2010;462:8-17 pubmed publisher
    ..Cultivation longer than 6 weeks leads to progressing dedifferentiation of chondrocytes that should be considered on long-term evaluations. ..
  9. Zhao X, Min C, Ko J, Parness J, Kim D, Weisleder N, et al. Increased store-operated Ca2+ entry in skeletal muscle with reduced calsequestrin-1 expression. Biophys J. 2010;99:1556-64 pubmed publisher
  10. Choi M, Saxena A, Chilukuri N. A strategy for the production of soluble human senescence marker protein-30 in Escherichia coli. Biochem Biophys Res Commun. 2010;393:509-13 pubmed publisher
    ..Our results pave the way for exploring the use of rHuSMP30 against organophosphate and nerve agent toxicity. ..
  11. Lai R, Arslan F, Lee M, Sze N, Choo A, Chen T, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4:214-22 pubmed publisher
    ..This novel role of exosomes highlights a new perspective into intercellular mediation of tissue injury and repair, and engenders novel approaches to the development of biologics for tissue repair. ..
  12. Yan C, Grimm W, Garner W, Qin L, Travis T, Tan N, et al. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol. 2010;176:2247-58 pubmed publisher
    ..In summary, we uncovered EMT features in both acute and fibrotic cutaneous wound healing of human skin. Moreover, we propose that the mesenchymal induction in wound healing is motivated by TNF-alpha, in part, through induction of BMP. ..
  13. Uitto J, Li Q, Jiang Q. Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms. J Invest Dermatol. 2010;130:661-70 pubmed publisher
    ..Understanding of the pathomechanistic details of PXE provides a basis for the development of targeted molecular therapies for this currently intractable disease...
  14. Yap S, Vafiadaki E, Strong J, Kontrogianni Konstantopoulos A. HAX-1: a multifaceted antiapoptotic protein localizing in the mitochondria and the sarcoplasmic reticulum of striated muscle cells. J Mol Cell Cardiol. 2010;48:1266-79 pubmed publisher
    ..Our findings are the first to present a comprehensive characterization of HAX-1's expression in striated muscles and to provide insights on the mechanisms through which it may modulate apoptosis. ..
  15. Ambler C, Watt F. Adult epidermal Notch activity induces dermal accumulation of T cells and neural crest derivatives through upregulation of jagged 1. Development. 2010;137:3569-79 pubmed publisher
    ..We conclude that jagged 1 is a key mediator of non-cell autonomous Notch signalling in skin...
  16. Kumada T, Yamanaka Y, Kitano A, Shibata M, Awaya T, Kato T, et al. Ttyh1, a Ca(2+)-binding protein localized to the endoplasmic reticulum, is required for early embryonic development. Dev Dyn. 2010;239:2233-45 pubmed publisher
    ..Our findings indicate that Ttyh1 plays an indispensable role during mitosis in early embryogenesis, possibly by maintaining Ca(2+) homeostasis in the ER. ..
  17. LARREA M, Wander S, Slingerland J. p27 as Jekyll and Hyde: regulation of cell cycle and cell motility. Cell Cycle. 2009;8:3455-61 pubmed
    ..Further characterization of post-translational modifications governing p27 localization and its action on RhoA and the actin cytoskeleton may provide critical insights into human cancer metastasis. ..
  18. Silveira T, Zamboni D. Pore formation triggered by Legionella spp. is an Nlrc4 inflammasome-dependent host cell response that precedes pyroptosis. Infect Immun. 2010;78:1403-13 pubmed publisher
    ..pneumophila specific nor the result of membrane damage induced by Dot/Icm activity; instead, it is a highly coordinated host cell response dependent on host Nlrc4 and caspase-1 and on bacterial flagellin and type IV secretion system. ..
  19. Galon Y, Aloni R, Nachmias D, Snir O, Feldmesser E, Scrase Field S, et al. Calmodulin-binding transcription activator 1 mediates auxin signaling and responds to stresses in Arabidopsis. Planta. 2010;232:165-78 pubmed publisher
    ..Thus, CAMTA1 participates in auxin signaling and responds to abiotic stresses. ..
  20. Ito T, Nakata M, Fukazawa J, Ishida S, Takahashi Y. Alteration of substrate specificity: the variable N-terminal domain of tobacco Ca(2+)-dependent protein kinase is important for substrate recognition. Plant Cell. 2010;22:1592-604 pubmed publisher
    ..Our results open the possibility of engineering the substrate specificity of CDPK by manipulation of the variable N-terminal domain, enabling a rational rewiring of cellular signaling pathways. ..
  21. Kuzontkoski P, Mulligan Kehoe M, Harris B, Israel M. Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels. Oncogene. 2010;29:3793-802 pubmed publisher
    ..Inhibition of MGP resulted in smaller and less vascularized xenografts. Our finding shows a novel function for ID4 in tumor angiogenesis, and identifies ID4 and MGP as possible therapeutic targets for GBM. ..
  22. Wang X, Tsai J, Imai J, Lian W, Vallee R, Shi S. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature. 2009;461:947-55 pubmed publisher
    ..These results indicate that preferential inheritance of the centrosome with the mature older mother centriole is required for maintaining radial glia progenitors in the developing mammalian neocortex...
  23. Shrivastava R, Williams A, Mikhail A, Roberts D, Richards M, Aithal V. An unusual cause of hypertension and renal failure: a case series of a family with Alagille syndrome. Nephrol Dial Transplant. 2010;25:1501-6 pubmed publisher
    ..This syndrome may cause symptomatic bradyarrhythmias as described in our series. ..
  24. Ma J, Meng Y, Kwiatkowski D, Chen X, Peng H, Sun Q, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 2010;120:103-14 pubmed publisher
    ..Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling. ..
  25. Li N, Jia N, Dai D, Hu C, Dai Y. Role of endothelin in the effects of isoprenaline on potassium currents and calsequestrin 2 expression in the heart. Clin Exp Pharmacol Physiol. 2010;37:557-63 pubmed publisher
    ..By suppressing the ISO-exaggerated I(Kr) and I(Ks) and normalizing the expression of CASQ2, endothelin receptor antagonism is likely promising in dealing with stress-related cardiac arrhythmias. ..
  26. Park H, Ishigami A, Shima T, Mizuno M, Maruyama N, Yamaguchi K, et al. Hepatic senescence marker protein-30 is involved in the progression of nonalcoholic fatty liver disease. J Gastroenterol. 2010;45:426-34 pubmed publisher
    ..These results suggest that hepatic SMP30 is closely associated with the pathogenesis of NAFLD, although it is not known whether decreased hepatic SMP30 is a result or a cause of cirrhosis. ..
  27. Shcherbakova O, Serebryanaya D, Postnikov A, Schroeter M, Zittrich S, Noegel A, et al. Kinase-related protein/telokin inhibits Ca2+-independent contraction in Triton-skinned guinea pig taenia coli. Biochem J. 2010;429:291-302 pubmed publisher
  28. Brun E, Blouquit Y, Duchambon P, Malosse C, Chamot Rooke J, Sicard Roselli C. Oxidative stress induces mainly human centrin 2 polymerisation. Int J Radiat Biol. 2010;86:657-68 pubmed publisher
    ..These results show that as oxidative radicals induce high proportions of irreversible damages (polymerisation) centrin 2 is highly sensitive to ionising radiation. This could have important consequences on its biological functions. ..
  29. Wang G, Lu S, Liu J, Guo C, Zhou Y, Yuan F, et al. [Phospholamban antisense RNA transfer attenuates post-infarction remodeling and preserves cardiac functions]. Zhonghua Yi Xue Za Zhi. 2010;90:1389-94 pubmed
  30. Park J, Ki M, Lee H, Hong I, Ji A, Ishigami A, et al. Vitamin C deficiency attenuates liver fibrosis by way of up-regulated peroxisome proliferator-activated receptor-gamma expression in senescence marker protein 30 knockout mice. Hepatology. 2010;51:1766-77 pubmed publisher
  31. Ke Y, Sheehan K, Egom E, Lei M, Solaro R. Novel bradykinin signaling in adult rat cardiac myocytes through activation of p21-activated kinase. Am J Physiol Heart Circ Physiol. 2010;298:H1283-9 pubmed publisher
    ..Our studies indicate a novel signaling mechanism for BK in adult rat cardiac myocytes and support our hypothesis that Pak 1 is a significant regulator of phosphatase activity in the heart. ..
  32. James S, Ranasinghe A, Venkateswaran R, McCabe C, Franklyn J, Bonser R. The effects of acute triiodothyronine therapy on myocardial gene expression in brain stem dead cardiac donors. J Clin Endocrinol Metab. 2010;95:1338-43 pubmed publisher
    ..5 and SERCA2a, but not ADRB1 or PLB and is not associated with any improvement in hemodynamic performance. ..
  33. Leon C, de Nijs L, Chanas G, Delgado Escueta A, Grisar T, Lakaye B. Distribution of EFHC1 or Myoclonin 1 in mouse neural structures. Epilepsy Res. 2010;88:196-207 pubmed publisher
    ..As discussed, this opens the door to a new conceptual approach viewing some idiopathic generalized epilepsies as developmental diseases instead of classical channelopathies. ..
  34. Hughes E, Edwards R, Middleton D. Heparin-derived oligosaccharides interact with the phospholamban cytoplasmic domain and stimulate SERCA function. Biochem Biophys Res Commun. 2010;401:370-5 pubmed publisher
    ..These results indicate that the cytoplasmic domain of PLB is functionally important and could be a valid target for compounds with drug-like properties. ..
  35. Chen H, Libertini S, Wang Y, Kung H, Ghosh P, Mudryj M. ERK regulates calpain 2-induced androgen receptor proteolysis in CWR22 relapsed prostate tumor cell lines. J Biol Chem. 2010;285:2368-74 pubmed publisher
    ..This suggests that a higher calpain/calpastatin ratio collaborates with activated ERK to promote the generation of the LMW-AR. ..
  36. Yamasaki K, Daiho T, Danko S, Suzuki H. Ca2+ release to lumen from ADP-sensitive phosphoenzyme E1PCa2 without bound K+ of sarcoplasmic reticulum Ca2+-ATPase. J Biol Chem. 2010;285:38674-83 pubmed publisher
    ..These findings show that bound K(+) is critical for stabilizing both E1PCa(2) and E2P structures, thereby contributing to the structural changes that efficiently couple phosphoenzyme processing and Ca(2+) handling. ..
  37. Trimarchi S, Sangiorgi G, Sang X, Rampoldi V, Suzuki T, Eagle K, et al. In search of blood tests for thoracic aortic diseases. Ann Thorac Surg. 2010;90:1735-42 pubmed publisher
  38. Shi X, Opi S, Lugari A, Restouin A, Coursindel T, Parrot I, et al. Identification and biophysical assessment of the molecular recognition mechanisms between the human haemopoietic cell kinase Src homology domain 3 and ALG-2-interacting protein X. Biochem J. 2010;431:93-102 pubmed publisher
    ..The structural framework of the Hck-Alix interaction will help to clarify how Hck and Alix assist during virus budding and cell-surface receptor regulation. ..
  39. Perocchi F, Gohil V, Girgis H, Bao X, McCombs J, Palmer A, et al. MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature. 2010;467:291-6 pubmed publisher
    ..Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease. ..
  40. Durak H, Comunoglu N, Comunoglu C, Guven A, Cam M, Dervisoglu S, et al. Specificity and sensitivity of differentiation antigens in superficial soft tissue tumors: comparison of SMA, calponin, H-caldesmon, C-kit, PLAP and HPL. Bratisl Lek Listy. 2010;111:432-8 pubmed
    ..05). Superficial soft tissue tumors did not express c-kit. In conclusion, HCD and PLAP can be used as ancillary immunomarkers in differential diagnosis of SMC tumors (Tab. 2, Fig. 7, Ref. 37). ..
  41. Kamikouchi A, Wiek R, Effertz T, Gopfert M, Fiala A. Transcuticular optical imaging of stimulus-evoked neural activities in the Drosophila peripheral nervous system. Nat Protoc. 2010;5:1229-35 pubmed publisher
    ..The method is exemplified for mechanosensory neurons in the adult antenna but can also be applied to many other PNS neurons, as is shown for the femoral chordotonal organ located in the fly's leg. ..
  42. Wooding F, Ramirez Pinilla M, Forhead A. Functional studies of the placenta of the lizard Mabuya sp. (Scincidae) using immunocytochemistry. Placenta. 2010;31:675-85 pubmed publisher
    ..The localization of these transporters demonstrated restricted distributions in the specialized areas of this morphologically complex placenta. ..
  43. Roumes H, Leloup L, Dargelos E, Brustis J, Daury L, Cottin P. Calpains: markers of tumor aggressiveness?. Exp Cell Res. 2010;316:1587-99 pubmed publisher
  44. Aldahmesh M, Al Owain M, Alqahtani F, Hazzaa S, Alkuraya F. A null mutation in CABP4 causes Leber's congenital amaurosis-like phenotype. Mol Vis. 2010;16:207-12 pubmed
  45. Wang H, Zhang J, Cui J, Tan X, Li W, Gu J, et al. Expression status of S100A14 and S100A4 correlates with metastatic potential and clinical outcome in colorectal cancer after surgery. Oncol Rep. 2010;23:45-52 pubmed
    ..001). Taken together, the signature derived from the combined expression status of S100A14 and S100A4 could be a valuable prognostic indicator in CRC. ..
  46. Samanta K, Kar P, Chakraborti T, Chakraborti S. Calcium-dependent cleavage of the Na(+)/Ca(2+) exchanger by m-calpain in isolated endoplasmic reticulum. J Biochem. 2010;147:225-35 pubmed publisher
    ..Cleavage of NCX1 by m-calpain in the ER may be interpreted as the main cause of intracellular Ca(2+) overload in the smooth muscle, which could be important for the manifestation of pulmonary hypertension. ..
  47. Stifanese R, Averna M, De Tullio R, Pedrazzi M, Beccaria F, Salamino F, et al. Adaptive modifications in the calpain/calpastatin system in brain cells after persistent alteration in Ca2+ homeostasis. J Biol Chem. 2010;285:631-43 pubmed publisher
  48. Lee C, Hwang I, Choi J, Yoo K, Han T, Park O, et al. Calcium binding proteins immunoreactivity in the rat basolateral amygdala following myocardial infarction. Cell Mol Neurobiol. 2010;30:333-8 pubmed publisher
    In this study, we examined changes in immunoreactivities of calcium binding proteins, such as parvalbumin (PV), calbindin (CB), and calretinin (CR), in the rat basolateral amygdala (BLA) 14 days after myocardial infarction (MI)...
  49. Sabourin J, Lamiche C, Vandebrouck A, Magaud C, Rivet J, Cognard C, et al. Regulation of TRPC1 and TRPC4 cation channels requires an alpha1-syntrophin-dependent complex in skeletal mouse myotubes. J Biol Chem. 2009;284:36248-61 pubmed publisher
    ..Cation channels with DAPC form a signaling complex that modulates cation entry and may be crucial for normal calcium homeostasis in skeletal muscles...
  50. Chung S, Kim J, Kim D, Kim J, Lee E, Anton S, et al. Molecular delineation of gamma-ray-induced NF-kappaB activation and pro-inflammatory genes in SMP30 knockout mice. Radiat Res. 2010;173:629-34 pubmed publisher
    ..Furthermore, our data revealed vitamin C may play an important protective role in attenuating the adverse gamma-radiation-induced adverse effects by suppressing adverse oxidative effects and pro-inflammatory mediators. ..
  51. Guescini M, Guidolin D, Vallorani L, Casadei L, Gioacchini A, Tibollo P, et al. C2C12 myoblasts release micro-vesicles containing mtDNA and proteins involved in signal transduction. Exp Cell Res. 2010;316:1977-84 pubmed publisher
    ..In particular, the present findings suggest possible new diagnostic approaches to skeletal muscle diseases. ..
  52. D Angelo A, Bluteau O, Garcia Gonzalez M, Gresh L, Doyen A, Garbay S, et al. Hepatocyte nuclear factor 1alpha and beta control terminal differentiation and cell fate commitment in the gut epithelium. Development. 2010;137:1573-82 pubmed publisher
    ..Our study identifies new direct target genes of the Hnf1 transcription factors and shows that they play crucial roles in both defining cell fate and controlling terminal functions in the gut epithelium. ..
  53. Xing Y, Qiu W, Ye J, Han L, Xu S, Zhang H, et al. [Studies on the clinical manifestation and SLC25A13 gene mutation of Chinese patients with neonatal intrahepatic cholestasis caused by citrin deficiency]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2010;27:180-5 pubmed publisher
    ..To investigate the clinical and laboratory features of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and to characterize the molecular basis and prognosis of this disease...