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Inactivating variants in PIEZO2, which encodes a stretch-gated ion channel, impair touch perception and proprioception. Visual cues partially compensate for these impairments, allowing affected persons to perform complex movements with greater accuracy. The ability to sense force, which is known as mechanosensation, provides humans and other animals with important information about the environment; it is crucial for social interactions, such as comforting or caressing, and is required for motor coordination. A number of anatomical classes of somatosensory neurons with distinct selectivity for mechanical stimuli have been identified, but the way in which these inputs combine to provide the richness of the human sense of touch remains unclear. 1 , 2 Similarly, proprioception is considered to be essential for posture and controlled movement, but little is known about the underlying mechanisms and the precise role . . .

Transcriptome data can facilitate the interpretation of the effects of rare genetic variants. Here, we introduce ANEVA (analysis of expression variation) to quantify genetic variation in gene dosage from allelic expression (AE) data in a population. Application of ANEVA to the Genotype-Tissues Expression (GTEx) data showed that this variance estimate is robust and correlated with selective constraint in a gene. Using these variance estimates in a dosage outlier test (ANEVA-DOT) applied to AE data from 70 Mendelian muscular disease patients showed accuracy in detecting genes with pathogenic variants in previously resolved cases and led to one confirmed and several potential new diagnoses. Using our reference estimates from GTEx data, ANEVA-DOT can be incorporated in rare disease diagnostic pipelines to use RNA-sequencing data more effectively.

Mutations in the LAMA2 gene affect the production of the α2 subunit of laminin-211 (= merosin) and result in either partial or complete laminin-211 deficiency. Complete merosin deficiency is typically associated with a more severe congenital muscular dystrophy, clinically manifested by hypotonia and weakness at birth, the development of contractures of large joints and progressive respiratory involvement. Muscle atrophy and severe weakness typically prevent independent ambulation. Partial merosin deficiency is mostly manifested by later onset limb-girdle weakness and joint contractures so that independent ambulation is typically achieved. Collectively, complete and partial merosin deficiency are referred to as LAMA2-related dystrophies (LAMA2-RDs) and represent one of most common forms of congenital muscular dystrophies worldwide. LAMA2-RDs are classically characterized by both central and peripheral nervous system involvement with abnormal appearing white matter on brain MRI and dystrophic appearing muscle on muscle biopsy as well as creatine kinase levels commonly elevated to > 1,000 IU/L. Next generation sequencing has greatly improved diagnostic abilities for LAMA2-RD, and the majority of patients with merosin deficiency carry recessive pathogenic variants in the LAMA2 gene. The existence of multiple animal models for LAMA2-RDs has helped to advance our understanding of laminin-211 and has been instrumental in preclinical research progress and translation to clinical trials. The first clinical trial for the LAMA2-RDs was a phase 1 pharmacokinetic and safety study of the anti-apoptotic compound omigapil, based on preclinical studies performed in the dyW/dyW and dy2J/dy2Jmouse models. This phase 1 study enabled the collection of pulmonary and motor outcome measures and also provided the opportunity for investigating exploratory outcome measures including muscle ultrasound, muscle MRI and serum and urine biomarker collection. Natural history studies, including a five-year prospective natural history and comparative outcome measures study in patients with LAMA2-RD, have helped to better delineate the natural history and identify viable outcome measures. Plans for further clinical trials for LAMA2-RDs are presently in progress, highlighting the necessity of identifying adequate, disease-relevant biomarkers, capable of reflecting potential therapeutic changes, in addition to refining the clinical outcome measures and time-to-event trajectory analysis of affected patients

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection. The mechanisms underlying deep pressure sensing are not fully understood. Here the authors demonstrate that while two individuals lacking Aβ fibers demonstrate impaired deep pressure sensing, seven individuals with PIEZO2 loss of function mutations display normal deep pressure responses.

•Since 2017, a number of clinical studies in centronuclear myopathies have taken place.•Focus groups were held with members of patient organizations in different countries.•The results provide insights in trial experiences and recommendations for future trials.•The acknowledgment of the patient perspective was strongly appreciated.•Efficient communication is expected to improve future clinical studies. Since 2014, several clinical studies focusing on centronuclear myopathies have been conducted, including a prospective natural history study, a gene transfer clinical trial and a clinical trial using an antisense oligonucleotide. Dedicated patient organizations have played an important role in this process. The experience of members of these organizations, either as a study participant, parent or as a patient organization member communicating with the sponsors are potentially very informative for future trial design. We investigated the burden of and the lessons learned from the first natural history studies and clinical trials from a patient perspective using a qualitative approach. We arranged 4 focus groups with a total of 37 participants from 3 large international patient organizations: ZNM-ZusammenStark!, the Myotubular Trust, and the MTM-CNM Family Connection. 4 themes, based on a systematic literature search were discussed: Expectations and preparation, Clinical study participation, Communication and Recommendations for future clinical trials. The focus group recordings were transcribed, anonymized, and uploaded to Atlas-ti version 8.1 software. The data were analyzed using a thematic content analysis. Overall, participants were realistic in their expectations, hoping for small improvements of function and quality of life. The realization that trial participation does not equate to a treatment was challenging. Participating in a clinical study had a huge impact on many aspects of daily life, both for patients and their immediate families. First-hand insights into the burden of the design and its possible effect on performance were provided, resulting in numerous compelling recommendations for future clinical studies. Furthermore, participants stressed the importance of clear communication, which was considered to be especially vital in cases of severe adverse events. Finally, while patients were understanding of the importance of adhering to the regulations of good clinical practice, they indicated that they would strongly appreciate a greater understanding and/or acknowledgment of the patient perspective and a reflection of this perspective in future clinical trial design. The acknowledgment and inclusion of patients’ perspectives and efficient and effective communication is expected to improve patient recruitment and retention in future clinical studies, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.

Michael Duchen, Francesco Muntoni, Eamonn Sheridan and colleagues show that loss-of-function mutations in MICU1 cause a recessive disorder characterized by proximal myopathy, learning difficulties and progressive extrapyramidal motor deficits. The mutations alter mitochondrial calcium homeostasis, leading to mitochondrial damage and dysfunction. Mitochondrial Ca 2+ uptake has key roles in cell life and death. Physiological Ca 2+ signaling regulates aerobic metabolism, whereas pathological Ca 2+ overload triggers cell death. Mitochondrial Ca 2+ uptake is mediated by the Ca 2+ uniporter complex in the inner mitochondrial membrane 1 , 2 , which comprises MCU, a Ca 2+ -selective ion channel, and its regulator, MICU1. Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder. In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca 2+ uptake at low cytosolic Ca 2+ concentrations was increased, and cytosolic Ca 2+ signals were reduced. Although resting mitochondrial membrane potential was unchanged in MICU1-deficient cells, the mitochondrial network was severely fragmented. Whereas the pathophysiology of muscular dystrophy 3 and the core myopathies 4 involves abnormal mitochondrial Ca 2+ handling, the phenotype associated with MICU1 deficiency is caused by a primary defect in mitochondrial Ca 2+ signaling, demonstrating the crucial role of mitochondrial Ca 2+ uptake in humans.

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.

After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities. Drawing on our experience as clinical investigators, basic scientists, and bioethicists involved in a first-in-human GT trial for an ultrarare pediatric disease, we analyze these ethical challenges and offer points to consider for future GT trials.

BET1 is required, together with its SNARE complex partners GOSR2, SEC22b, and Syntaxin‐5 for fusion of endoplasmic reticulum‐derived vesicles with the ER‐Golgi intermediate compartment (ERGIC) and the cis ‐Golgi. Here, we report three individuals, from two families, with severe congenital muscular dystrophy (CMD) and biallelic variants in BET1 (P1 p.(Asp68His)/p.(Ala45Valfs*2); P2 and P3 homozygous p.(Ile51Ser)). Due to aberrant splicing and frameshifting, the variants in P1 result in low BET1 protein levels and impaired ER‐to‐Golgi transport. Since in silico modeling suggested that p.(Ile51Ser) interferes with binding to interaction partners other than SNARE complex subunits, we set off and identified novel BET1 interaction partners with low affinity for p.(Ile51Ser) BET1 protein compared to wild‐type, among them ERGIC‐53. The BET1/ERGIC‐53 interaction was validated by endogenous co‐immunoprecipitation with both proteins colocalizing to the ERGIC compartment. Mislocalization of ERGIC‐53 was observed in P1 and P2’s derived fibroblasts; while in the p.(Ile51Ser) P2 fibroblasts specifically, mutant BET1 was also mislocalized along with ERGIC‐53. Thus, we establish BET1 as a novel CMD/epilepsy gene and confirm the emerging role of ER/Golgi SNAREs in CMD. SYNOPSIS This study describes three individuals with a progressive early‐onset congenital muscular dystrophy, and additional epilepsy in one, caused by biallelic variants in the BET1 gene. BET1, along with its SNARE complex partners, is essential for ER‐to‐Golgi trafficking. In Family 1, compound heterozygous variants p.(Asp68His)/p.(Ala45Valfs*2) cause aberrant splicing and frameshifting, resulting in very low BET1 protein levels. Variants in Family 2 (homozygous p.(Ile51Ser)) do not impact BET1 protein levels, interactions with ER‐to‐Golgi SNARE complex members, or SNARE function in yeast. Mutant Ile51Ser BET1 shows massively reduced binding of the novel Bet1 interaction partner ERGIC‐53, which is also mislocalized in patient fibroblasts. There is a significant slowing of Golgi‐reconstitution in patient fibroblasts and impaired ER‐to‐Golgi trafficking in HeLa cells. This study adds to the emerging role of ER/Golgi SNARE dysfunction in the causation of muscular dystrophy. Graphical Abstract This study describes three individuals with a progressive early‐onset congenital muscular dystrophy, and additional epilepsy in one, caused by biallelic variants in the BET1 gene. BET1, along with its SNARE complex partners, is essential for ER‐to‐Golgi trafficking.

Objectives To investigate the consequences of a pathogenic missense variant (c.838C>T; p.L280F) and a 5′‐UTR regulatory variant (c.‐122G>T) in BCS1L on disease pathogenesis and to understand how regulatory variants influence disease severity and clinical presentation. Methods Deep phenotyping, research‐based whole genome sequencing, biochemical characterization of identified variants, and studies in patient‐derived fibroblast cultures were applied to uncover the underlying genetic cause and molecular defects in siblings with a genetically uncharacterized complex neurologic condition. Results Genome sequencing identified a paternally inherited missense variant (c.838C>T; p.L280F) and a maternally inherited 5′‐UTR variant (c.‐122G>T) in BCS1L in two affected siblings. Although the missense variant disrupts complex III assembly, the 5′‐UTR variant allows residual wild‐type BCS1L expression, likely mitigating disease severity. Biochemical studies in patient‐derived fibroblasts confirmed the pathogenicity of both variants and demonstrated a moderate in vitro response to a coenzyme Q10 analog. Interpretation This study expands the clinical spectrum of BCS1L‐related disorders to include a comparatively milder phenotype with central and peripheral nervous system involvement. Our findings demonstrate that the 5′‐UTR variant modulates disease severity by enabling residual wild‐type BCS1L expression, partially mitigating the pathogenic effects of the missense variant. These insights underscore the importance of evaluating both protein coding and regulatory variants in mitochondrial disease diagnostics and pathogenesis.