The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

Abstract: Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRSMini and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)—retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)—mild ID, p.(Pro167Thr)—high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. Key messages: The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder.p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions.Phenotypic heterogeneity associates with the different affected YARS1 domains.Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders

Antibiotic adjuvants: synergistic tool to combat multi-drug resistant pathogens

The rise of multi-drug resistant (MDR) pathogens poses a significant challenge to the field of infectious disease treatment. To overcome this problem, novel strategies are being explored to enhance the effectiveness of antibiotics. Antibiotic adjuvants have emerged as a promising approach to combat MDR pathogens by acting synergistically with antibiotics. This review focuses on the role of antibiotic adjuvants as a synergistic tool in the fight against MDR pathogens. Adjuvants refer to compounds or agents that enhance the activity of antibiotics, either by potentiating their effects or by targeting the mechanisms of antibiotic resistance. The utilization of antibiotic adjuvants offers several advantages. Firstly, they can restore the effectiveness of existing antibiotics against resistant strains. Adjuvants can inhibit the mechanisms that confer resistance, making the pathogens susceptible to the action of antibiotics. Secondly, adjuvants can enhance the activity of antibiotics by improving their penetration into bacterial cells, increasing their stability, or inhibiting efflux pumps that expel antibiotics from bacterial cells. Various types of antibiotic adjuvants have been investigated, including efflux pump inhibitors, resistance-modifying agents, and compounds that disrupt bacterial biofilms. These adjuvants can act synergistically with antibiotics, resulting in increased antibacterial activity and overcoming resistance mechanisms. In conclusion, antibiotic adjuvants have the potential to revolutionize the treatment of MDR pathogens. By enhancing the efficacy of antibiotics, adjuvants offer a promising strategy to combat the growing threat of antibiotic resistance. Further research and development in this field are crucial to harness the full potential of antibiotic adjuvants and bring them closer to clinical application

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function

Pilot study of the application of magnetic bead protein profiling to the study of biomarkers in addiction research

Proteomic technologies based on mass spectrometry are increasingly used as a valuable tool in clinical research allowing high-throughput protein and peptide profiling to be undertaken. Whilst previous research has focussed the application of this novel technology on the study of patients with disorders compared to comparable individuals from the healthy population, this current study seeks to determine the effect of successful treatment for alcoholism on the serum protein profile obtained