Article Text
Abstract
Complete and limited proteolysis represents key events that regulate many biological processes. At least 5% of the human genome codes for components of proteolytic processes if proteases, inhibitors, and cofactors are taken into account. Accordingly, disruption of proteolysis is involved in numerous pathological conditions. In particular, molecular genetic studies have identified a growing number of monogenic disorders caused by mutations in protease coding genes, highlighting the importance of this class of enzymes in development, organogenesis, immunity, and brain function. This review provides insights into the current knowledge about the molecular genetic causes of these disorders. It should be noted that most are due to loss of function mutations, indicating absolute requirement of proteolytic activities for normal cellular functions. Recent progress in understanding the function of the implicated proteins and the disease pathogenesis is detailed. In addition to providing important clues to the diagnosis, treatment, and pathophysiology of disease, functional characterisation of mutations in proteolytic systems emphasises the pleiotropic functions of proteases in the body homeostasis.
- ADAMTS, a disintegrin and metalloproteinase with thrombospondin-like motifs
- ALPSII, autoimmune lymphoproliferative syndrome type II
- APP, amyloid precursor protein
- CFI, complement factor I
- CLN2, neuronal late infantile ceroid lipofuscinosis
- CNS, central nervous system
- DISC, death inducing signalling complex
- DUB, de-ubiquitinating enzymes
- ECE-1, endothelin converting enzyme 1
- ECM, extracellular matrix
- ENaC, epithelial amiloride sensitive sodium channel
- GCSF, granulocyte colony stimulating factor
- GCSFR, granulocyte colony stimulating factor receptor
- HSCR, Hirschsprung’s disease
- IKK, IκB kinase
- LDLR, low density lipoprotein receptor
- LGMD2A, limb girdle muscular dystrophy type 2A
- MAD, mandibuloacral dysplasia
- MASP2, mannan binding lectin serine protease 2
- MMP, matrix metalloproteases
- NARC1, neural apoptosis regulated convertase
- NE, neutrophil elastase 2
- NFκB, nuclear factor kappa B
- PCSK9, proconvertase 9
- PHEX, phosphate regulating gene with homologies to endopeptidases located on the X chromosome
- RIP, regulated intramembrane proteolysis Aβ, amyloid β peptides
- SPG7, spastic paraplegia
- SUMO, small ubiquitin-like modifier
- TMPRSS3, transmembrane protease, serine 3
- TTP, thrombotic thrombocytopenic purpura
- UCH, ubiquitin C terminal hydrolase
- USP, ubiquitin specific processing protease
- UCHL1, ubiquitin carboxyterminal esterase L1
- VWF, von Willebrand factor
- XLH, X linked hypophosphataemia
- monogenic disease
- mutation
- protease
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- ADAMTS, a disintegrin and metalloproteinase with thrombospondin-like motifs
- ALPSII, autoimmune lymphoproliferative syndrome type II
- APP, amyloid precursor protein
- CFI, complement factor I
- CLN2, neuronal late infantile ceroid lipofuscinosis
- CNS, central nervous system
- DISC, death inducing signalling complex
- DUB, de-ubiquitinating enzymes
- ECE-1, endothelin converting enzyme 1
- ECM, extracellular matrix
- ENaC, epithelial amiloride sensitive sodium channel
- GCSF, granulocyte colony stimulating factor
- GCSFR, granulocyte colony stimulating factor receptor
- HSCR, Hirschsprung’s disease
- IKK, IκB kinase
- LDLR, low density lipoprotein receptor
- LGMD2A, limb girdle muscular dystrophy type 2A
- MAD, mandibuloacral dysplasia
- MASP2, mannan binding lectin serine protease 2
- MMP, matrix metalloproteases
- NARC1, neural apoptosis regulated convertase
- NE, neutrophil elastase 2
- NFκB, nuclear factor kappa B
- PCSK9, proconvertase 9
- PHEX, phosphate regulating gene with homologies to endopeptidases located on the X chromosome
- RIP, regulated intramembrane proteolysis Aβ, amyloid β peptides
- SPG7, spastic paraplegia
- SUMO, small ubiquitin-like modifier
- TMPRSS3, transmembrane protease, serine 3
- TTP, thrombotic thrombocytopenic purpura
- UCH, ubiquitin C terminal hydrolase
- USP, ubiquitin specific processing protease
- UCHL1, ubiquitin carboxyterminal esterase L1
- VWF, von Willebrand factor
- XLH, X linked hypophosphataemia
Footnotes
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Competing interests: none declared