Meta-Biol

• Pathways

Lafora disease is a progressive neurodegenerative disorder with onset typically late in childhood, characterized by seizures and progressive neurological deterioration and death within ten years of onset. Recessive mutations in EPM2A (laforin) and NHLRC1 (malin) have been identified as causes of the disease. The disease is classified here as one of glycogen storage as EPM2A (laforin) and NHLRC1 (malin) regulate normal glycogen turnover and defects in either protein are associated with the formation of Lafora bodies, accumulations of abnormal, insoluble glycogen molecules in tissues including brain, muscle, liver, and heart (Ramachandran et al. 2009; Roach et al. 2012). Consistent with a central role for glycogen accumulation in the disease, reduced (Turnbull et al. 2011) or absent (Pederson et al. 2013) glycogen synthase activity prevents Lafora Disease in mouse models.

Type 2A disease. EPM2A (laforin) associated with cytosolic glycogen granules, normally catalyzes the removal of the phosphate groups added rarely but consistently to growing glycogen molecules (Tagliabracci et al. 2011). Defects in this catalytic activity lead to the formation of phosphorylated glycogen molecules that are insoluble and that show abnormal branching patterns (Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011).

Type 2B disease. NHLRC1 (malin) normally mediates polyubiquitination of EPM2A (laforin) and PPP1R3C (PTG). The two polyubiquitinated proteins are targeted for proteasome-mediated degradation, leaving a glycogen-glycogenin particle associated with glycogen synthase. In the absence of NHLRC1 activity, EPM2A and PPP1R3C proteins appear to persist, associated with the formation of abnormal, stable glycogen granules (Lafora bodies) (Chan et al. 2003; Gentry et al. 2005). In NHLRC1 knockout mice PPP1R3C levels are unchanged rather than increased, suggesting that NHLRC1 does not target PPP1R3C for degradation. However, EPM2A protein levels are increased in this knockout consistent with NHLRC1's proposed role (DePaoli-Roach et al. 2010).

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. Mutations that disrupt these processes by inactivating a required enzyme or regulatory protein, or more rarely by changing its specificity can lead to severe diseases. Metabolic diseases annotated here involve aspects of carbohydrate, glycosylation, amino acid (phenylketonuria), surfactant and vitamin metabolism, and biological oxidations. One somatic mutation that affects cytosolic isocitrate metabolism, often found in glioblastomas and some lymphoid neoplasms, is also annotated. Also described are mutated forms of adrenocorticotropic hormone (ACTH) that can lead to obesity, resulting in excessive accumulation of body fat.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.