Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

Bott et al. here reports that de novo and biallelic variants in ATP6V0A1 gene affect the ability of the V-ATPase complex to translocate protons and acidify the endolysosomal compartment in neurons, causing a severe neurological phenotype ranging from developmental and epileptic encephalopathy to progressive myoclonus epilepsy. The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.Peer reviewe

Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype 2 by modulating AR transcriptional activity:AR isoform 2 counteracts polyglutamine AR toxicity

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR-dysregulated transcriptional activity

Mutations in CCDC 39 and CCDC 40 are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed ‘radial spoke defect’. We sequenced CCDC39 and CCDC40 in 54 ‘radial spoke defect’ families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice and frameshift predicting early protein truncation, which suggests this defect is caused by ‘null’ alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganisation and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as ‘IDA and nexin-dynein regulatory complex (N-DRC) defect’, rather than ‘radial spoke defect’

“Jag behöver dom” En kvalitativ studie om familjens betydelse för ensamkommande barn i Sverige

Denna studies syfte var att undersöka och beskriva ensamkommande ungdomars upplevelser av att vara separerade från familj samt deras hantering och tankar kring familj på distans. Studiens frågeställningar var: Vad har separation inneburit för ungdomarna, hur påverkas ungdomarna av kontakten med familjerna och hur sker deras hantering av att ha familj på distans, vad har ungdomarna för tankar kring familjeåterförening och till sist hur tillgodoses socialt stöd för ungdomarna i och med att familjerna befinner sig på distans. Data insamlades med en kvalitativ forskningsintervju med fem ungdomar som kommit som ensamkommande barn till Sverige. Intervjuerna har analyserats med hjälp av teorierna och begreppen: anknytningsteorin, socialt stöd, coping och skuld. Slutsatserna i denna studie var att separationer från familjerna har inneburit svårigheter för ungdomarna som tänker mycket på sina familjer och oroar sig för dem. Detta påverkar deras tillvaro i Sverige. Samtliga ungdomar har kontakt med sina familjer vilket påverkar deras vardag både positivt men också negativt i och med mer saknad och längtan efter familjerna. Ingen av ungdomarna har ännu återförenats med familjerna men har en önskan om en återförening. Slutligen visar studien att det finns en brist på socialt stöd för flera av ungdomarna som mår dåligt i och med att familjerna befinner på distans

Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene.

Mutations, mostly in the region of the COL10A1 gene encoding the C-terminal non-collagenous domain, cause the dwarfism metaphyseal chondrodysplasia type Schmid (MCDS). In most cases, the disease mechanism involves the misfolding of the mutant protein causing increased endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). However, in an iliac crest biopsy, the COL10A1 p.Y632X mutation was found to produce instability of the mutant mRNA such that little mutant protein may be produced. To investigate the disease mechanism further, a gene-targeted mouse model of the Col10a1 p.Y632X mutation was generated. In this model, the mutant mRNA showed no instability, and in mice heterozygous for the mutation, mutant and wild-type mRNAs were present at equal concentrations. The protein was translated from the mutant allele and retained within the cell, triggering increased ER stress and a UPR. The mutation produced a relatively severe form of MCDS. Nevertheless, treatment of the mice with carbamazepine (CBZ), a drug which stimulates intracellular proteolysis and alleviates ER stress, effectively reduced the disease severity in this model of MCDS caused by a premature stop codon in the Col10a1 gene. Specifically, the drug reduced ER stress in the growth plate, restored growth plate architecture toward the wild-type state, significantly increased bone growth and within 2 weeks of treatment corrected the MCDS-induced hip distortion. These results indicate that CBZ is likely to be effective in ongoing clinical trials against all forms of MCDS whether caused by premature stop codons or substitutions.ISSN:0964-6906ISSN:1460-208

Paradoxical roles of ATF6α and ATF6β in modulating disease severity caused by mutations in collagen X

Whilst the role of ATF6α in modulating the unfolded protein response (UPR) has been well documented, the function of its paralogue ATF6β is less well understood. Using knockdown in cell culture and gene ablation in mice we have directly compared the roles of ATF6α & β in responding to the increased ER stress induced by mutant forms of type X collagen that cause the ER stress-associated metaphyseal chondrodysplasia type Schmid (MCDS). ATF6α more efficiently deals with the disease-associated ER stress in the absence of ATF6β and conversely, ATF6β is less effective in the absence of ATF6α. Furthermore, disease severity in vivo is increased by ATF6α ablation and decreased by ATF6β ablation. In addition, novel functions for each paralogue are described including an ATF6β-specific role in controlling growth plate chondrocyte proliferation. The clear demonstration of the intimate relationship of the two ATF6 isoforms and how ATF6β can moderate the activity of ATF6α and vice versa is of great significance for understanding the UPR mechanism. The activities of both ATF6 isoforms and their separate roles need consideration when deciding how to target increased ER stress as a means of treating MCDS and other ER stress-associated diseases