Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.

OBJECTIVE: To identify the cause of isolated distal weakness in a family with both neuropathic and myopathic features on EMG and muscle histology. METHODS: Case study with exome sequencing in 2 affected individuals, bioinformatic prioritization of genetic variants, and segregation analysis of the likely causal mutation. Functional studies included Western blot analysis of the candidate protein before and after heat shock treatment of primary skin fibroblasts. RESULTS: A novel HSPB1 variant (c.387C>G, p.Asp129Glu) segregated with the phenotype and was predicted to alter the conserved α-crystallin domain common to small heat shock proteins. At baseline, there was no difference in HSPB1 protein levels nor its binding partner αB-crystallin. Heat shock treatment increased HSPB1 protein levels in both patient-derived and control fibroblasts, but the associated increase in αB-crystallin expression was greater in patient-derived than control fibroblasts. CONCLUSIONS: The HSPB1 variant (c.387C>G, p.Asp129Glu) is the likely cause of distal neuromyopathy in this pedigree with pathogenic effects mediated through binding to its partner heat shock protein αB-crystallin. Mutations in HSBP1 classically cause a motor axonopathy, but this family shows that the distal weakness can be both myopathic and neuropathic. The traditional clinical classification of distal weakness into "myopathic" or "neuropathic" forms may be misleading in some instances, and future treatments need to address the pathology in both tissues.This study was funded by Wellcome Trust (101876/Z/13/Z and 096919Z/11/Z), Medical Research Council (UK) (G0601943), and Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). Funding bodies had no influence on study design or data interpretation.This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/NXG.000000000000011

Questionnaire study to gain an insight into the manufacturing and fitting process of artificial eyes in children: an ocularist perspective

Purpose To gain an insight into the manufacturing and fitting of artificial eyes in children and potential improvements to the process. Method An online qualitative survey was distributed to 39 ocularists/prosthetists in Europe and Canada. Participants were recruited through purposive sampling, specifically maximum variation sampling from the researcher’s contacts and an online search. Results The findings highlighted the current impression technique as being the most difficult yet most important part of the current process for both the ocularist and child patient. Negatively affecting obtaining a good impression, the child patients distress can be reduced by their parents by providing encouragement, reassurance, practicing the insertion and removal of the artificial eye and being matter of fact. Whilst improvements to the current process provided mixed views, the incorporation of current technology was perceived as not being able to meet the requirements to produce aesthetically pleasing artificial eyes. Conclusion The current artificial eye process can be seen as an interaction with its success being dependent on the child patient’s acceptance and adjustment which is dependent on the factors associated to the process. Investigation into the needs of the patient and whether technology can improve the process are the next steps in its advancement

MFN2 mutations cause compensatory mitochondrial DNA proliferation.

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot–Marie–Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy ‘plus’ phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A&gt;T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with ‘mitochondrial DNA breakage’ syndrome. Contrary to previous studies in patients with Charcot–Marie–Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. <br/

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

Problems of literary reform in modern China.

The period following the fall of the Manchu dynasty in 1911 was one of rapid economic and social change in China. It created conditions favourable for the development of the New Culture Movement which started during the Great war, and reached its climax in 1919.Two of the basic features of this movement were the introduction of ideas from the West and the reassessment of Chinese traditions from the standpoint of those ideas. The Literary Revolution was an integral part of the New Culture Movement, which, after an initial period of discussion and debate, undertook the task of building a new Chinese literature with a new humanist or revolutionary content, and with forms copied from, or inspired by. Western literature. The problems which this task of construction involved were many and varied. During the next few years the literature of many periods and countries was introduced into China, and the new writers experimented with numerous forms. Ultimately, those which accorded most closely with the needs of Chinese literature, and especially with the social conditions and demands of the Chinese revolution, which had a determining influence on it, were successfully adopted, and fused with the Chinese tradition. The writer who best succeeded in mastering these problems of selection and synthesis was Lu Hsun, who, while benefiting from the example of Western writers, especially Russian, at the same time retained a Chinese character and style, not only through the subject matter of his work, but also from his knowledge and keen appreciation of old Chinese literature

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photo-receptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.Foundation Fighting Blindness CanadaCanadian Institutes of Health ResearchNIHCharles University institutional programmesBIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development FundMinistry of Health of the Czech RepublicGraduate School of Life Sciences (University of Wuerzburg)Government of Canada through Genome CanadaOntario Genomics InstituteGenome QuebecGenome British ColumbiaMcLaughlin CentreCharles Univ Prague, Inst Inherited Metab Disorders, Fac Med 1, Prague 12000 2, Czech RepublicMcGill Univ, Dept Human Genet, Fac Med, Montreal, PQ H3A 0G1, CanadaGenome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, CanadaClin Res Inst Montreal, Cellular Neurobiol Res Unit, Montreal, PQ H2W 1R7, CanadaMcGill Univ, Montreal, PQ H3A 0G4, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, McGill Ocular Genet Lab, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Paediat Surg, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Human Genet, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Ophthalmol, Montreal, PQ H3H 1P3, CanadaUniv Alberta, Royal Alexandra Hosp, Dept Ophthalmol & Visual Sci, Edmonton, AB T5H 3V9, CanadaCharles Univ Prague, Inst Biol & Med Genet, Fac Med 1, Prague 12000 2, Czech RepublicBaylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USAUniversidade Federal de São Paulo, Dept Neurol, Div Gen Neurol, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol, Ataxia Unit, BR-04021001 São Paulo, BrazilNewcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, EnglandUniversidade Federal de São Paulo, Dept Ophthalmol, BR-04021001 São Paulo, BrazilSo Gen Hosp, Dept Clin Genet, Glasgow G51 4TF, Lanark, ScotlandCardiff Univ, Sch Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, WalesHadassah Hebrew Univ Med Ctr, Dept Ophthalmol, IL-91120 Jerusalem, IsraelOregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97239 USAUniv Wurzburg, Lehrstuhl Neurobiol & Genet, D-97074 Wurzburg, GermanyUniv Montreal, Dept Med, Montreal, PQ H3T 1P1, CanadaMcGill Univ, Dept Anat & Cell Biol, Div Expt Med, Montreal, PQ H3A 2B2, CanadaUniversidade Federal de São Paulo, Dept Neurol, Div Gen Neurol, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol, Ataxia Unit, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ophthalmol, BR-04021001 São Paulo, BrazilNIH: EY022356-01NIH: EY018571-05NIH: NS047663-09Charles University institutional programmes: PRVOUK-P24/LF1/3Charles University institutional programmes: UNCE 204011Charles University institutional programmes: SVV2013/266504BIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development Fund: CZ.1.05/1.1.00/02.0109Ministry of Health of the Czech Republic: NT13116-4/2012Ministry of Health of the Czech Republic: NT14015-3/2013Ontario Genomics Institute: OGI-049Web of Scienc