SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA

Myoclonus-dystonia syndrome (MDS) is a genetically heterogeneous disorder characterized by myoclonic jerks often seen in combination with dystonia and psychiatric co-morbidities and epilepsy. Mutations in the gene encoding epsilon-sarcoglycan (SGCE) have been found in some patients with MDS. SGCE is a maternally imprinted gene with the disease being inherited in an autosomal dominant pattern with reduced penetrance upon maternal transmission. In the central nervous system, epsilon-sarcoglycan is widely expressed in neurons of the cerebral cortex, basal ganglia, hippocampus, cerebellum and the olfactory bulb. epsilon-Sarcoglycan is located at the plasma membrane in neurons, muscle and transfected cells. To determine the effect of MDS-associated mutations on the function of epsilon-sarcoglycan we examined the biosynthesis and trafficking of wild-type and mutant proteins in cultured cells. In contrast to the wild-type protein, disease-associated epsilon-sarcoglycan missense mutations (H36P, H36R and L172R) produce proteins that are undetectable at the cell surface and are retained intracellularly. These mutant proteins become polyubiquitinated and are rapidly degraded by the proteasome. Furthermore, torsinA, that is mutated in DYT1 dystonia, a rare type of primary dystonia, binds to and promotes the degradation of epsilon-sarcoglycan mutants when both proteins are co-expressed. These data demonstrate that some MDS-associated mutations in SGCE impair trafficking of the mutant protein to the plasma membrane and suggest a role for torsinA and the ubiquitin proteasome system in the recognition and processing of misfolded epsilon-sarcoglycan

Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

One of Us? How do Developing Market Professionals Engage with International Communities of Practice?

Much focus has been given in recent years to the Community of Practice, Participation Metaphor of Learning. Less attention has been paid in the literature to understanding the elements effecting how people are able to engage, particularly within the dynamic of developing market professionals within international CoP’s. This study explores the experiences and perceptions of established international professional’s and newcomers within this dynamic. Through qualitative investigation in two organisations in West Africa and the Middle East, the study discusses findings within two meta themes regarding the effects of local newcomer’s experiences of legitimate peripheral participation in their respective CoP’s. Firstly “Multiple and Consistent Identity Formation within CoP Constellation Navigation” explores two-way meaning and learning from professional communities and the impact on actors developing professional and personal identities. This is built from four contributory themes; Exploring different routes to CoP participation; Impacts of professional vs domestic CoP’s on identity; Continuity of personal identity across CoP’s and the impact of CoP norms on Identity. Secondly “Palatable Diversity” explores evidence around the impact of sponsored participation opportunities; Positive discrimination policies, Effects of local CoP members becoming established; Degrees of diversity found palatable by established Professionals, and finally: An absence of Racism in LPP. Conclusions are made that engagement in LPP is entirely possible through a nuanced understanding of individual differences within a complex landscape of CoP’s, which is notably different for developing market newcomers in comparison to their international predecessors. This impacts on their professional and personal identities in different ways. It was however found that access was attainable to them, if they succeeded in understanding and navigating the trajectories required for participation by established members. This is presented as providing a contribution to the debate through problematizing recent literature on multiple identity creation through meaning making in legitimate peripheral participation, as well as adding to the discussion on attitudes to diversity within a constellation landscape of international and local CoP’s

The neurobiology of the dystrophin-associated glycoprotein complex

While the function of dystrophin in muscle disease has been thoroughly investigated, dystrophin and associated proteins also have important roles in the central nervous system. Many patients with Duchenne and Becker muscular dystrophies (D/BMD) have cognitive impairment, learning disability, and an increased incidence of some neuropsychiatric disorders. Accordingly, dystrophin and members of the dystrophin-associated glycoprotein complex (DGC) are found in the brain where they participate in macromolecular assemblies that anchor receptors to specialized sites within the membrane. In neurons, dystrophin and the DGC participate in the postsynaptic clustering and stabilization of some inhibitory GABAergic synapses. During development, -dystroglycan functions as an extracellular matrix receptor controlling, amongst other things, neuronal migration in the developing cortex and cerebellum. Several types of congenital muscular dystrophy caused by impaired -dystroglycan glycosylation cause neuronal migration abnormalities and mental retardation. In glial cells, the DGC is involved in the organization of protein complexes that target water-channels to the plasma membrane. Finally, mutations in the gene encoding ε-sarcoglycan cause the neurogenic movement disorder, myoclonus-dystonia syndrome implicating εsarcoglycan in dopaminergic neurotransmission. In this review we describe the recent progress in defining the role of the DGC and associated proteins in the brain

A gain-of-glycosylation mutation associated with myoclonus-dystonia syndrome affects trafficking and processing of mouse ε-sarcoglycan in the late secretory pathway

Missense mutations in the SGCE gene encoding ε-sarcoglycan account for approximately 15% of SGCE-positive cases of myoclonus-dystonia syndrome (MDS) in humans. In this study, we show that while the majority of MDS-associated missense mutants modeled with a murine ε-sarcoglycan cDNA are substrates for endoplasmic reticulum-associated degradation, one mutant, M68T (analogous to human c.275T>C, p.M92T), located in the Ig-like domain of ε-sarcoglycan, results in a gain-of-glycosylation mutation producing a protein that is targeted to the plasma membrane, albeit at reduced levels compared to wild-type ε-sarcoglycan. Removal of the ectopic N-linked glycan failed to restore efficient plasma membrane targeting of M68T demonstrating that the substitution rather than the glycan was responsible for the trafficking defect of this mutant. M68T also colocalized with CD63-positive vesicles in the endosomal–lysosomal system and was found to be more susceptible to lysosomal proteolysis than wild-type ε-sarcoglycan. Finally, we demonstrate impaired ectodomain shedding of M68T, a process that occurs physiologically for ε-sarcoglycan resulting in the lysosomal trafficking of the intracellular C-terminal domain of the protein. Our findings show that functional analysis of rare missense mutations can provide a mechanistic insight into the pathogenesis of MDS and the physiological role of ε-sarcoglycan

Recent advances in the genetics of the ALS-FTLD complex

There is a clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of autosomal-dominant genes have been described that primarily cause ALS or FTLD such as progranulin (GRN), valosin-containing protein (VCP), and TAR DNA-Binding Protein (TARDBP), and for each of these conditions there are a small number of cases with both ALS and FTLD. Two major genes were described in 2011, which cause FTLD and/or ALS within extended kindreds. Ubiquilin2 (UBQLN2) is responsible for X-linked FTLD/ALS. A hexanucleotide repeat expansion in C9ORF72 causes chromosome 9p linked FTLD/ALS and is the most common cause of familial ALS accounting for about 40 % of familial cases. Both UBQLN2 and C9ORF72 mutations lead to TDP-43 positive neuropathology, and C9ORF72-positive cases have p62/ubiquitin-positive pathology, which is not stained by TDP-43 antibodies. Ubiquilin2 is one of a family of proteins thought to be important in targeting abnormal proteins for degradation via lysosomal and proteasomal routes. The pathogenic mechanism of the C9ORF72 expansion is unknown but may involve partial haploinsufficiency of C9ORF72 and/or the formations of toxic RNA inclusions. The identification of mutations in these genes represents an important step forward in our understanding of the clinical, pathological, and genetic spectrum of ALS/FTLD diseases

Psychiatric disorders, myoclonus dystonia, and the epsilon-sarcoglycan gene: a systematic review

Background: Mutations in the maternally imprinted epsilon-sarcoglycan gene occur in 30%–50% of myoclonus-dystonia cases. Psychiatric symptoms, particularly obsessive-compulsive disorder, have been described in some patients. Methods: We systematically reviewed 22 reports of psychiatric symptoms in myoclonus-dystonia, dividing individuals according to clinical and mutation status. Results: Clinically manifesting mutation carriers demonstrated an excess of psychiatric disorders compared with nonmutation carriers (P < .001). No differences were seen between non-motor-manifesting carriers and nonmutation carriers with the exception of alcohol excess/dependence, higher in non-motor-manifesting carriers. Conclusions: The results confirm the association of epsilon-sarcoglycan gene mutations with psychiatric disease and suggest a possible separation of the motor and psychiatric effects

Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p

Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression