The Role of PIEZO2 in Human Mechanosensation Chesler, Alexander T; Szczot, Marcin; Bharucha-Goebel, Diana ...
The New England journal of medicine,
10/2016, Letnik:
375, Številka:
14
Journal Article
Recenzirano
Odprti dostop
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.
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Similarly, proprioception is considered to be essential for posture and controlled movement, but little is known about the underlying mechanisms and the precise role . . .
OBJECTIVES:Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).
METHODS:Patients were enrolled at 3 study sites and followed for up to ...36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.
RESULTS:Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p = 0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n = 10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Childrenʼs Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21–2.33, p = 0.02).
CONCLUSIONS:Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.
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.
Skeletal muscle function relies on the myofibrillar apparatus inside myofibers as well as an intact extracellular matrix surrounding each myofiber. Muscle extracellular matrix (ECM) plays several ...roles including but not limited to force transmission, regulation of growth factors and inflammatory responses, and influencing muscle stem cell (i.e. satellite cell) proliferation and differentiation. In most myopathies, muscle ECM undergoes remodeling and fibrotic changes that may be maladaptive for normal muscle function and recovery. In addition, mutations in skeletal muscle ECM and basement proteins can cause muscle disease. In this review, we summarize the clinical features of two of the most common congenital muscular dystrophies, COL6-related dystrophies and LAMA2-related dystrophies, which are caused by mutations in muscle ECM and basement membrane proteins. The study of clinical features of these diseases has helped to inform basic research and understanding of the biology of muscle ECM. In return, basic studies of muscle ECM have provided the conceptual framework to develop therapeutic interventions for these and other similar disorders of muscle.
•COL6-related dystrophies and LAMA2-related dystrophies are prototypical diseases of muscle extracellular matrix.•Early-onset and progressive large joint contractures are prominent in these dystrophies.•Study of extramuscular features of these diseases, including joint contractures, should be included in future studies.•Non-invasive ventilatory support is an essential part of clinical management of most patients with COL6-RDs and LAMA2-RDs.•Delineation of the ECM role in disease mechanism has primed several therapeutic strategies for these disorders.
Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a ...lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.
Dystroglycanopathies: coming into focus Godfrey, Caroline; Foley, A Reghan; Clement, Emma ...
Current opinion in genetics & development,
06/2011, Letnik:
21, Številka:
3
Journal Article
Recenzirano
A common group of muscular dystrophies is associated with the aberrant glycosylation of α-dystroglycan. These clinically heterogeneous disorders, collectively termed dystroglycanopathies, are often ...associated with central nervous system and more rarely eye pathology. Defects in a total of eight putative and demonstrated glycosyltransferases or accessory proteins of glycosyltransferases have been shown to cause a dystroglycanopathy phenotype. In recent years the systematic analysis of large patient cohorts has uncovered a complex relationship between the underlying genetic defect and the resulting clinical phenotype. These studies have also drawn attention to the high proportion of patients that remain without a genetic diagnosis implicating novel genes in the pathogenesis of dystroglycanopathies. Recent glycomic analyses of α-dystroglycan have reported complex patterns of glycan composition and have uncovered novel glycan modifications. The exact glycan synthesis and modification pathways involved, as well as their role in ligand binding, remain only partially characterised. This review will focus on recent studies that have extended our knowledge of the mechanisms underlying dystroglycanopathies and have further characterised this patient population.
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.
Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of ...the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia.
Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly ...progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.
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, 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 and the core myopathies 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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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