RESUMEN

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.

RESUMEN

Recapping of Varroa destructor-infested brood cells is a trait that has recently attracted interest in honey bee breeding to select mite-resistant Apis mellifera colonies. To investigate the genetic architecture of this trait, we evaluated a sample of A. mellifera mellifera colonies (N = 155) from Switzerland and France and performed a genome-wide association study, using a pool of 500 workers per colony for next-generation sequencing. The results revealed that two QTL were significantly (P < 0.05) associated with recapping of V. destructor-infested brood cells. The best-associated QTL is located on chromosome 5 in a region previously found to be associated with grooming behaviour, a resistance trait against V. destructor, in A. mellifera and Apis cerana. The second best-associated QTL is located on chromosome 4 in an intron of the Dscam gene, which is involved in neuronal wiring. Previous research demonstrated that genes involved in neuronal wiring are associated with recapping and varroa sensitive hygiene. Therefore, our study confirms the role of a gene region on chromosome 5 in social immunity and simultaneously provides novel insights into genetic interactions between common mite resistance traits in honey bees.

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RESUMEN

Atxn10 is a gene known for its role in cytokinesis and is associated with spinocerebellar ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes nephronophthisis (NPHP) and Joubert syndrome (JBTS), which are caused by the disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here, we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue-specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt ATXN10 systemically at postnatal stages, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial-to-mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively, this study identifies ATXN10 as an essential protein for survival.

RESUMEN

SIL1 is a ubiquitous protein of the Endoplasmic Reticulum (ER) acting as a co-chaperone for the ER-resident chaperone, BiP. Recessive mutations of the corresponding gene lead to vulnerability of skeletal muscle and central nervous system in man (Marinesco-Sjögren syndrome; MSS) and mouse. However, it is still unclear how loss of ubiquitous SIL1 leads to selective vulnerability of the nervous system and skeletal muscle whereas other cells and organs are protected from clinical manifestations. In this study we aimed to disentangle proteins participating in selective vulnerability of SIL1-deficient cells and tissues: morphological examination of MSS patient-derived lymphoblastoid cells revealed altered organelle structures (ER, nucleus and mitochondria) thus showing subclinical vulnerability. To correlate structural perturbations with biochemical changes and to identify proteins potentially preventing phenotypical manifestation, proteomic studies have been carried out. Results of proteomic profiling are in line with the morphological findings and show affection of nuclear, mitochondrial and cytoskeletal proteins as well as of such responsible for cellular viability. Moreover, expression patterns of proteins known to be involved in neuromuscular disorders or in development and function of the nervous system were altered. Paradigmatic findings were confirmed by immunohistochemistry of splenic lymphocytes and the cerebellum of SIL1-deficient mice. Ataxin-10, identified with increased abundance in our proteome profile, is necessary for the neuronal survival but also controls muscle fiber apoptosis, thus declaring this protein as a plausible candidate for selective tissue vulnerability. Our combined results provide first insights into the molecular causes of selective cell and tissue vulnerability defining the MSS phenotype.

RESUMEN

OBJECTIVES: Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown. METHODS AND RESULTS: By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven "cachexokines", including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models. CONCLUSIONS: As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia.