Dissection of the Carboxyl-Terminal Domain of the Proteasomal Subunit Rpn11 in Maintenance of Mitochondrial Structure and Function

We have previously demonstrated that the C-terminal part of Rpn11, a deubiquitinating enzyme in the lid of the proteasome, is essential for maintaining a correct cell cycle and normal mitochondrial morphology and function. The two roles are apparently unlinked as the mitochondrial role is mapped to the Carboxy-terminus, whereas the catalytic deubiquitinating activity is found within the N-terminal region. The mitochondrial defects are observed in rpn11-m1 (originally termed mpr1-1), a mutation that generates Rpn11 lacking the last 31 amino acids. No mitochondrial phenotypes are recorded for mutations in the MPN/JAMM motif. In the present study, we investigated the participation of the last 31 amino acids of the Rpn11 protein by analysis of intragenic revertants and site-specific mutants. We identified a putative -helix necessary for the maintenance of a correct cell cycle and determined that a very short region at the C-terminus of Rpn11 is essential for the maintenance of tubular mitochondrial morphology. Furthermore, we show that expression of the C-terminal part of Rpn11 is able to complement in trans all of the rpn11-m1 mitochondrial phenotypes. Finally, we investigate the mechanisms by which Rpn11 controls the mitochondrial shape and show that Rpn11 may regulate the mitochondrial fission and tubulation processes

Peripheral facial palsy following ventriculoperitoneal shunt. The lesson we have learned

The most frequent complications after shunt surgery are infective and obstructive. Other types are less common, and eventually occur due to technical errors during brain ventricular puncture, opening the intraperitoneal cavity or the tunnelling of the catheter between the two points. Although rare, there are well-reported complications related to the poor positioning of the distal catheter, with perforation of organs and tissues. We report a very rare case of a male patient with normal pressure hydrocephalus submitted to ventriculoperitoneal shunt. During tunnelling of the shunt stylet, a peripheral facial palsy due to injury to the extra cranial segment of the facial nerve occurred. To the best of our knowledge this is the second case described in Literature. The patient and the surgeon should be aware of this very rare but possible complication in shunt surgery being careful to the course of the facial nerve in the mastoid region

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Nucleo-mitochondrial interactions in Saccharomyces cerevisiae: characterisation of a nuclear gene suppressing a defect in mitochondrial tRNAAsp processing.

We utilized the heat-sensitive mutant strain (Ts932), bearing a mutation at position 61 in the mitochondrial tRNAAsp gene, to identify nuclear genes involved in tRNA biogenesis; this mutant is defective in 30-end processing and consequently in the production of mature mitochondrial tRNAAsp. We transformed this strain with a yeast nuclear library and we isolated among other suppressors, an unknown, nonessential gene (called SMM1, corresponding to open reading frame YNR015w), which restored the growth on glycerol and a normal amount of processed tRNAAsp in the mutant. The gene contains a domain highly conserved in evolution from bacteria to human and its product has been recently shown to have dihydrouridine synthase activity