Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Methionine adenosyltransferase I/III deficiency: beyond the central nervous system manifestations

Marwan Nashabat,1 Sultan Al-Khenaizan,2 Majid Alfadhel1 1King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia; 2Department of Dermatology, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia Abstract: Methionine adenosyltransferase (MAT) I/III deficiency (OMIM # 250850) is caused by a mutation in MAT1A, which encodes the two hepatic MAT isozymes I and III. With the implementation of newborn screening program to discover hypermethioninemia due to cystathionine beta-synthase deficiency, more cases are being discovered. While the majority of patients are asymptomatic, some might have central nervous system (CNS) and extra-CNS manifestations. Although neurologic manifestations and demyelination have been correlated to MAT deficiency in many reported cases, none of the previous reports focused on extra-CNS manifestations associated with the disease. This is a retrospective chart review for a 40-month-old patient with confirmed diagnosis of MAT deficiency. He was found to have a novel homozygous disease-causing variant in MAT1A (NM_000429.2) c.1081G>T (p.Val361Phe). Interestingly, our patient had an unexplained zinc and iron deficiency in addition to mild speech delay. We reviewed the literature and summarized all the reported extra-CNS manifestations. In conclusion, MAT deficiency patients should be thoroughly investigated to check for CNS and extra-CNS manifestations associated with the disease. Keeping in consideration the challenge of assuming correlation, a scrutinized look at extra-CNS manifestations and their course with time might pave the way to understanding the pathophysiology of the disease and MAT1A function. Keywords: MAT1A, methionine adenosyltransferase, S-adenosyl methionine, central nervous system&nbsp