Pathway: Loss of phosphorylation of MECP2 at T308
Loss of phosphorylation of MECP2 at T308
Disorders of nervous system development affect the function of the central nervous system (CNS) and impair motor skills, cognition, communication and/or behavior (reviewed by Ismail and Shapiro 2019). So far,we have annotated the role of loss-of-function mutations in methyl-CpG-binding protein 2 (MECP2), an epigenetic regulator of transcription, in Rett syndrome, a pervasive developmental disorder (Pickett and London 2005, Ferreri 2014).
Disorders of myogenesis are rare hereditary muscle diseases that in the case of congenital myopathies are defined by architectural abnormalities in the muscle fibres (Pelin and Wallgren-Pettersson 2019, Phadke 2019, Radke et al. 2019, Claeys 2020) and in the case of muscular dystrophies by increased muscle breakdown that progresses with age (Pasrija and Tadi 2020). Mutations in cadherin family genes are present in some types of muscular dystrophy (Puppo et al. 2015).
Disorders of pancreas development result in pancreatic agenesis, where a critical mass of pancreatic tissue is congenitally absent. For example, the PDX1 gene is a master regulator of beta cell differentiation and homozygous deletions or inactivating mutations in PDX1 gene cause whole pancreas agenesis. PDX1 gene haploinsufficiency impairs glucose tolerance and leads to development of diabetes mellitus (Hui and Perfetti 2002, Babu et al. 2007, Chen et al. 2008).
Left-right asymmetry disorders are caused by mutations in genes that regulate the characteristic asymmetry of internal organs in vertebrates. Normally, cardiac apex, stomach and spleen are positioned towards the left side, while the liver and gallbladder are on the right. Loss-of-function mutations in the CFC1 gene, whose protein product functions as a co-factor in Nodal signaling, result in heterotaxic phenotype in affected patients, manifested by randomized organ positioning (Bamford et al. 2000).
Congenital lipodystrophies are characterized by a lack of adipose tissue, which predisposes affected patient to development of insulin resistance and related metabolic disorders. The severity of metabolic complications is correlates with the extent of adipose tissue loss. Loss-of-function mutations in the PPARG gene, encoding a key transcriptional regulator of adipocyte development and function, are a well-established cause of familial partial lipodystrophy type 3 (FPLD3) (Broekema et al. 2019).
Congenital stem cell disorders are caused by mutations in genes that regulate the balance between stem cells maintenance and commitment to differentiated lineages. Loss-of-function mutations in the SOX2 gene, which encodes a transcription factor involved in the maintenance of totipotency during embryonic preimplantation period, pluripotency of embryonic stem cells, and multipotency of neural stem cells, are the cause of anophthalmia (the absence of an eye) and microphthalmia (the presence of a small eye within the orbit (Verma and Fitzpatrick 2007, Sarlak and Vincent 2016).
HOX-related structural birth defects are caused by loss-of-function mutations in HOX family genes.HOX transcription factors play a fundamental role in body patterning during embryonic development, and HOX mutation are an underlying cause of many congenital limb malformations (Goodman 2002).
Congenital keratinization disorders are caused by dominant negative mutation in keratin genes and depending on where the affected keratin gene is expressed, they affect epithelial tissues such as skin, cornea, hair and/or nails (McLean and Moore 2011).
Disorders of immune system development are caused by mutations in genes that regulate differentiation of blood cell lineages involved in immune defense, leading to immune system defects. For example, mutations in the gene encoding CSF3R, a receptor for the granulocyte-colony stimulating factor, result in congenital neutropenia, characterized by a maturation arrest of granulopoiesis at the level of promyelocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections from an early age and may be predisposed to myelodysplastic syndromes or acute myeloid leukemia (Germeshausen et al. 2008; Skokowa et al. 2017).
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.