Anthropogenic climate change poses a serious threat to biodiversity. In marine environments, multiple climate variables, including temperature and CO₂ concentration (CO₂), are changing ...simultaneously. Although temperature has well-documented ecological effects, and many heavily calcified marine organisms experience reduced growth with increased CO₂, little is known about the combined effects of temperature and CO₂, particularly on species that are less dependent on calcified shells or skeletons. We manipulated water temperature and CO₂ to determine the effects on the sea star Pisaster ochraceus, a keystone predator. We found that sea star growth and feeding rates increased with water temperature from 5 °C to 21 °C. A doubling of current CO₂ also increased growth rates both with and without a concurrent temperature increase from 12 °C to 15 °C. Increased CO₂ also had a positive but nonsignificant effect on sea star feeding rates, suggesting CO₂ may be acting directly at the physiological level to increase growth rates. As in past studies of other marine invertebrates, increased CO₂ reduced the relative calcified mass in sea stars, although this effect was observed only at the lower experimental temperature. The positive relationship between growth and CO₂ found here contrasts with previous studies, most of which have shown negative effects of CO₂ on marine species, particularly those that are more heavily calcified than P. ochraceus. Our findings demonstrate that increased CO₂ will not have direct negative effects on all marine invertebrates, suggesting that predictions of biotic responses to climate change should consider how different types of organisms will respond to changing climatic variables.
Arthrogryposis multiplex congenita is defined by the presence of contractures across two or more major joints and results from reduced or absent fetal movement. Here, we present three consanguineous ...families affected by lethal arthrogryposis multiplex congenita. By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126. GPR126 encodes G-protein-coupled receptor 126, which has been shown to be essential for myelination of axons in the peripheral nervous system in fish and mice. A previous study reported that Gpr126−/− mice have a lethal arthrogryposis phenotype. We have shown that the peripheral nerves in affected individuals from one family lack myelin basic protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral axons during fetal development. Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling, and our biochemical assays indicated that the missense substitution (p.Val769Glu c.2306T>A) impairs autoproteolytic cleavage of GPR126. Our data indicate that GPR126 is critical for myelination of peripheral nerves in humans. This study adds to the literature implicating defective axoglial function as a key cause of severe arthrogryposis multiplex congenita and suggests that GPR126 mutations should be investigated in individuals affected by this disorder.
Body size plays a crucial role in determining the strength of species interactions, population dynamics, and community structure. We measured how changes in body size affect the trophic relationship ...between the sea star Pisaster ochraceus and its prey, the mussel Mytilus trossulus. We tested the effects of a wide range of predator and prey sizes on sea stars' prey-size preference, feeding rate, and prey tissue consumption. We found that preferred prey size increased with sea star size. Pisaster consumption rate (mussels consumed per day) and tissue intake rate (grams of tissue consumed per day) also increased with sea star size. Pisaster consumption rate, but not tissue intake rate, decreased with increasing mussel size. Juvenile sea stars preferred the most profitable prey sizes—that is, those that maximized tissue consumed per unit handling time. When adult sea stars were offered larger, more profitable mussels, tissue intake rates (grams per day) tended to increase, although this relationship was not statistically significant. Our results indicate that the Pisaster-Mytilus interaction depends on the sizes of both predator and prey, that predation rates are sensitive to even small changes in body size, and that shifts in size distributions may affect predator energetics and prey numbers differently depending on the factors that limit tissue consumption rates.
Objective
To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center.
Methods
We designed two iterations of a comprehensive targeted gene panel for ...neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used TargetSeqTM probe‐based hybridization for target enrichment followed by Ion Torrent sequencing. Targeted high‐coverage sequencing and analysis was performed on 2249 neurology patients from Australia and New Zealand (1054 Version 1, 1195 Version 2) from 2012 to 2015. No selection criteria were used other than referral from a suitable medical specialist (e.g., neurologist or clinical geneticist). Patients were classified into 15 clinical categories based on the clinical diagnosis from the referring clinician.
Results
Six hundred and sixty‐five patients received a genetic diagnosis (30%). Diagnosed patients were significantly younger that undiagnosed patients (26.4 and 32.5 years, respectively; P = 4.6326E‐9). The diagnostic success varied markedly between disease categories. Pathogenic variants in 10 genes explained 38% of the disease burden. Unexpected phenotypic expansions were discovered in multiple cases. Triage of unsolved cases for research exome testing led to the discovery of six new disease genes.
Interpretation
A comprehensive targeted diagnostic panel was an effective method for neuromuscular disease diagnosis within the context of an Australasian referral center. Use of smaller disease‐specific panels would have precluded diagnosis in many patients and increased cost. Analysis through a centralized laboratory facilitated detection of recurrent, but under‐recognized pathogenic variants.
Hereditary motor and sensory neuropathies, to which Charcot-Marie-Tooth (CMT) disease belongs, are a common cause of disability in adulthood. Growing awareness that axonal loss, rather than ...demyelination per se, is responsible for the neurological deficit in demyelinating CMT disease has focused research on the mechanisms of early development, cell differentiation, and cell-cell interactions in the peripheral nervous system. Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT, and understanding their molecular basis may provide a new perspective on these mechanisms. Here we report the identification of the gene responsible for hereditary motor and sensory neuropathy–Lom (HMSNL). HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis. The gene was previously mapped to 8q24.3, where conserved disease haplotypes suggested genetic homogeneity and a single founder mutation. We have reduced the
HMSNL interval to 200 kb and have characterized it by means of large-scale genomic sequencing. Sequence analysis of two genes located in the critical region identified the founder
HMSNL mutation: a premature-termination codon at position 148 of the
N-myc downstream-regulated gene 1 (
NDRG1).
NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. We have studied expression in peripheral nerve and have detected particularly high levels in the Schwann cell. Taken together, these findings point to
NDRG1 having a role in the peripheral nervous system, possibly in the Schwann-cell signaling necessary for axonal survival.
Distal myopathies are a group of clinically and pathologically overlapping muscle diseases that are genetically complex and can represent a diagnostic challenge. Laing early‐onset distal myopathy ...(MPD1) is a form of distal myopathy caused by mutations in the MYH7 gene, which encodes the beta myosin heavy chain protein expressed in type 1 skeletal muscle fibers and cardiac myocytes. Here, we present a case of genetically confirmed MPD1 with a typical clinical presentation but distinctive light microscopic and ultrastructural findings on muscle biopsy. A 39‐year‐old professional male cellist presented with a bilateral foot drop that developed by age 8; analysis of the family pedigree showed an autosomal dominant pattern of inheritance. The physical exam demonstrated bilateral weakness of ankle dorsiflexors, toe extensors and finger extensors; creatine kinase level was normal. Biopsy of the quadriceps femoris muscle showed predominance and hypotrophy of type 1 fibers, hybrid fibers with co‐expression of slow and fast myosin proteins (both in highly atrophic and normal size range), moth‐eaten fibers and mini‐cores, lack of rimmed vacuoles and rare desmin‐positive eosinophilic sarcoplasmic inclusions. In addition to these abnormalities often observed in MPD1, the biopsy demonstrated frequent clefted fibers with complex sarcolemmal invaginations; on ultrastructural examination, these structures closely mimicked myotendinous junctions but were present away from the tendon and were almost exclusively found in type 1 fibers. Sequencing analysis of the MYH7 gene in the index patient and other affected family members demonstrated a previously described heterozygous c.4522_4524delGAG (p.Glu1508del) mutation. This case widens the pathologic spectrum of MPD1 and highlights the pathologic and clinical variability that can accompany the same genetic mutation, suggesting a significant role for modifier genes in MPD1 pathogenesis.
Objective
This study sought to estimate the prevalence of depression and anxiety in UK college students and examine associations between mental health symptoms and quality of life (QoL). Associations ...between psychiatric comorbidity and degree of QoL impairment were also investigated. Participants: Participants (N = 286) were recruited from a UK university (76.1% ≤20 years-old; 86.8% female; 71.1% White). Methods: Self-report measures of depression, anxiety, and QoL were completed online. Group differences and within-group associations were examined with Chi-square analyses, linear regressions, and ANOVAs. Results: Prevalence rates were in line with global estimates and suggest female students are at elevated risk of mental health problems. Symptom severity and comorbidity were associated with greater QoL impairment. Conclusions: Presence of depression, anxiety, or both was associated with QoL impairment. Findings develop understanding of the impact of mental health problems on QoL and could inform appropriate screening and effective interventions for student mental health.
We investigated the manifestations of CMT4C disease in a genetically homogeneous group of patients homozygous for the recently identified Gypsy founder mutation p.Arg1109X in SH3TC2. We observed a ...surprising degree of variation in age at onset, rate of progression, extent and severity of motor and sensory involvement, scoliosis, and cranial nerve involvement, suggesting that the phenotypic spectrum of CMT4C disease is much broader than the classical diagnostic criteria. Phenotype similarity in first degree relatives and increasing heterogeneity in more distantly related subjects point to the involvement of genetic modifiers, possibly variants in the genes encoding protein partners interacting with SH3TC2.
Congenital cataracts-facial dysmorphism-neuropathy syndrome (CCFDN, MIM: 604168), is a recently delineated neurogenetic disease causing recurrent episodes of rhabdomyolysis; prevention and early ...diagnosis of rhabdomyolysis should be part of the clinical management of the disease.
ABSTRACT
Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/β‐cardiac myosin heavy chain encoded by the gene MYH7, as is a common form of familial ...hypertrophic/dilated cardiomyopathy. The mechanisms by which different phenotypes are produced by mutations in MYH7, even in the same region of the gene, are not known. To explore the clinical spectrum and pathobiology, we screened the MYH7 gene in 88 patients from 21 previously unpublished families presenting with distal or generalized skeletal muscle weakness, with or without cardiac involvement. Twelve novel mutations have been identified in thirteen families. In one of these families, the father of the proband was found to be a mosaic for the MYH7 mutation. In eight cases, de novo mutation appeared to have occurred, which was proven in four. The presenting complaint was footdrop, sometimes leading to delayed walking or tripping, in members of 17 families (81%), with other presentations including cardiomyopathy in infancy, generalized floppiness, and scoliosis. Cardiac involvement as well as skeletal muscle weakness was identified in nine of 21 families. Spinal involvement such as scoliosis or rigidity was identified in 12 (57%). This report widens the clinical and pathological phenotypes, and the genetics of MYH7 mutations leading to skeletal muscle diseases.
Twenty one previously unpublished families were shown to have an MYH7 gene mutation causing Laing distal myopathy (MPD1). Typical findings included footdrop and dropped fingers. Cardiac involvement was seen in 9, and spinal involvement in 12. Thirteen of these families had multiple affected members, but eight cases had no family history and de novo mutation was proven in four. A mosaic carrier was also identified. Twelve of the 21 mutations were novel.
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