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Protein misfolding is a common basis of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Misfolded proteins, such as TDP-43, FUS, Matrin3, and SOD1, mislocalize and form the hallmark cytoplasmic and nuclear inclusions in neurons of ALS patients. Cellular protein quality control prevents protein misfolding under normal conditions and, particularly, when cells experience protein folding stress due to the fact of increased levels of reactive oxygen species, genetic mutations, or aging. Molecular chaperones can prevent protein misfolding, refold misfolded proteins, or triage misfolded proteins for degradation by the ubiquitin–proteasome system or autophagy. DnaJC7 is an evolutionarily conserved molecular chaperone that contains both a J-domain for the interaction with Hsp70s and tetratricopeptide domains for interaction with Hsp90, thus joining these two major chaperones' machines. Genetic analyses reveal that pathogenic variants in the gene encoding DnaJC7 cause familial and sporadic ALS. Yet, the underlying ALS-associated molecular pathophysiology and many basic features of DnaJC7 function remain largely unexplored. Here, we review aspects of DnaJC7 expression, interaction, and function to propose a loss-of-function mechanism by which pathogenic variants in DNAJC7 contribute to defects in DnaJC7-mediated chaperoning that might ultimately contribute to neurodegeneration in ALS. [ABSTRACT FROM AUTHOR]

Background Heparan sulfate proteoglycans are vital components of the extracellular matrix and are essential for cellular homeostasis. Many genes are involved in modulating heparan sulfate synthesis, and when these genes are mutated, they can give rise to early-onset developmental disorders affecting multiple body systems. Herein, we describe a consanguineous family of four sibs with a novel disorder, which we designate as seizures-scoliosis- macrocephaly syndrome, characterised by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction. Methods Our application of autozygosity mapping and whole-exome sequencing allowed us to identify mutations in the patients. To confirm the autosomal-recessive mode of inheritance, all available family members were genotyped. We also studied the effect of these mutations on protein expression and function in patient cells and using an in vitro system. Results We identified two homozygous mutations p.Met87Arg and p.Arg95 Cys in exostosin 2, EXT2, a ubiquitously expressed gene that encodes a glycosyltransferase required for heparan sulfate synthesis. In patient cells, we observed diminished EXT2 expression and function. We also performed an in vitro assay to determine which mutation has a larger effect on protein expression and observed reduced EXT2 expression in constructs expressing either one of the mutations but a greater reduction when both residues were mutated. Conclusions In short, we have unravelled the genetic basis of a new recessive disorder, seizures-scoliosis-macrocephaly syndrome. Our results have implicated a well-characterised gene in a new developmental disorder and have further illustrated the spectrum of phenotypes that can arise due to errors in glycosylation. [ABSTRACT FROM AUTHOR]

Epilepsy affects approximately 1% of the world's population. Genetic factors and acquired etiologies, as well as a range of environmental triggers, together contribute to epileptogenesis. We have identified a family with three daughters affected with progressive myoclonus epilepsy with ataxia. Clinical details of the onset and progression of the neurologic presentation, epileptic seizures, and the natural history of progression over a 10-year period are described. Using autozygosity genetic mapping, we identified a high likelihood homozygous region on chromosome 7p12.1-7q11.22. We subsequently applied whole-exome sequencing and employed a rare variant prioritization analysis within the homozygous region. We identified p.Tyr276Cys in the potassium channel tetramerization domain-containing seven gene, KCTD7, which is expressed predominantly in the brain. Mutations in this gene have been implicated previously in epileptic phenotypes due to disturbances in potassium channel conductance. Pathogenicity of the mutation was supported by bioinformatic predictive analyses and variant cosegregation within the family. Further biologic validation is necessary to fully characterize the pathogenic mechanisms that explain the phenotypic causes of epilepsy with ataxia in these patients. [ABSTRACT FROM AUTHOR]