Background: Carpal tunnel syndrome (CTS) is a socially and economically relevant disease caused by compression or entrapment of the median nerve within the carpal tunnel. This population-based case-control study aims to investigate occupational/non-occupational risk factors for surgically treated CTS.

ContextLeber hereditary optic neuropathy (LHON) is a maternally inherited loss of central vision related to pathogenic mutations in the mitochondrial genome, which are a necessary but not sufficient condition to develop the disease. Investigation of precipitating environmental/occupational (and additional genetic) factors could be relevant for prevention.Case presentationAfter a 6-month period of occupational exposure to n-hexane and other organic solvents, a 27-year-old man (a moderate smoker) developed an optic neuropathy. The patient had a full ophthalmologic and neurologic investigation, including standardized cycloergometer test for serum lactic acid levels and a skeletal muscle biopsy. His exposure history was also detailed, and he underwent genetic testing for LHON mitochondrial DNA mutations. The patient suffered a sequential optic neuropathy with the hallmarks of LHON and tested positive for the homoplasmic 11778G → A/ND4 mutation. Routine laboratory monitoring revealed increased concentrations of urinary 2.5 hexandione (n-hexane metabolite) and hippuric acid (toluene metabolite) in the period immediately preceding the visual loss.DiscussionIn a subject carrying an LHON mutation, the strict temporal sequence of prolonged appreciable occupational exposure followed by sudden onset of visual loss must raise a suspicion of causality (with a possible further interaction with tobacco smoke).RelevanceIn this article, we add to the candidate occupational/environmental triggers of LHON and highlight the need for appropriate case–control (and laboratory) studies to validate the causal effect of mixed toxic exposures.

In mammals, meiotic recombination is initiated by the introduction of DNA double strand breaks (DSBs) into narrow segments of the genome, defined as hotspots, which is carried out by the SPO11/TOPOVIBL complex. A major player in the specification of hotspots is PRDM9, a histone methyltransferase that, following sequence-specific DNA binding, generates trimethylation on lysine 4 (H3K4me3) and lysine 36 (H3K36me3) of histone H3, thus defining the hotspots. PRDM9 activity is key to successful meiosis, since in its absence DSBs are redirected to functional sites and synapsis between homologous chromosomes fails. One protein factor recently implicated in guiding PRDM9 activity at hotspots is EWS, a member of the FET family of proteins that also includes TAF15 and FUS/TLS. Here, we demonstrate that FUS/TLS partially colocalizes with PRDM9 on the meiotic chromosome axes, marked by the synaptonemal complex component SYCP3, and physically interacts with PRDM9. Furthermore, we show that FUS/TLS also interacts with REC114, one of the axis-bound SPO11-auxiliary factors essential for DSB formation. This finding suggests that FUS/TLS is a component of the protein complex that promotes the initiation of meiotic recombination. Accordingly, we document that FUS/TLS coimmunoprecipitates with SPO11 in vitro and in vivo. The interaction occurs with both SPO11β and SPO11α splice isoforms, which are believed to play distinct functions in the formation of DSBs in autosomes and male sex chromosomes, respectively. Finally, using chromatin immunoprecipitation experiments, we show that FUS/TLS is localized at H3K4me3-marked hotspots in autosomes and in the pseudo-autosomal region, the site of genetic exchange between the XY chromosomes.

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