Meta-Biol

• Pathways

Mucopolysaccharidosis II (MPS II, Hunter syndrome, MIM:309900) is an X-linked, recessive genetic disorder which therefore primarily affects males. MPS II was first described in 1917, by Major Charles Hunter (Hunter 1917) and is caused by a deficiency (or absence) of iduronate-2-sulfatase (IDS, MIM:300823), which would normally hydrolyse the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin. Without IDS, these GAGs accumulate in the body and are excessively excreted in urine. Although the disease was known since the early 1970s, being the first MPS to be defined clinically in humans, it wasn't until the 1990s that IDS was cloned. It is now known to be localized to Xq28 (Wilson et al. 1991) and contain 9 exons (Flomen et al. 1993) spanning approximately 24 kb (Wilson et al. 1993).
Build up can occur in the liver and spleen as well as in the walls and valves of the heart (reduced hepatic and cardiac function, liver/spleen hepatosplenomegaly), airways (leading to obstructive airway disease), all major joints and bones (joint stiffness and skeletal deformities) and in brain (severe mental retardation). The rate of progression and degree of severity of the disorder can be different for each person with MPS II. Severe forms of the disorder can result in death in childhood whereas those with a "milder" form can expect to live to their 20's or 30's. Some patients even survive into their fifth and sixth decades of life (Wraith et al. 2008, Beck 2011).

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.