PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
1.  Erratum to 
Autophagy  2012;8(7):1163.
doi:10.4161/auto.21428
PMCID: PMC3429560
Lafora disease; autophagy; glycogen metabolism; laforin; malin; neurodegeneration
2.  C3 glomerulopathy–associated CFHR1 mutation alters FHR oligomerization and complement regulation  
The Journal of Clinical Investigation  2013;123(6):2434-2446.
C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H–related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G.
doi:10.1172/JCI68280
PMCID: PMC3668852  PMID: 23728178
3.  Impaired autophagy in Lafora disease 
Autophagy  2010;6(7):991-993.
Lafora disease (LD) is a progressive, lethal, autosomal recessive, neurodegenerative disorder that manifests with myoclonus epilepsy. LD is characterized by the presence of intracellular inclusion bodies called Lafora bodies (LB), in brain, spinal cord and other tissues. More than 50 percent of LD is caused by mutations in EPM2A that encodes laforin. Here we review our recent findings that revealed that laforin regulates autophagy. We consider how autophagy compromise may predispose to LB formation and neurodegeneration in LD, and discuss future investigations suggested by our data.
doi:10.4161/auto.6.7.13308
PMCID: PMC3039746  PMID: 20818165
autophagy; glycogen metabolism; Lafora disease; laforin; malin; neurodegeneration
4.  Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation  
The Journal of Clinical Investigation  2010;120(10):3702-3712.
Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C3923ΔDG, which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H2O) by spontaneous thioester hydrolysis, C3923ΔDG generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C3b923ΔDG and C3(H2O)923ΔDG were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase–restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments.
doi:10.1172/JCI43343
PMCID: PMC2947238  PMID: 20852386
5.  C3 glomerulopathy: consensus report 
Kidney International  2013;84(6):1079-1089.
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
doi:10.1038/ki.2013.377
PMCID: PMC3842953  PMID: 24172683
clinical immunology; clinical nephrology; complement; glomerulonephritis; immunology and pathology

Results 1-5 (5)