Dystrophins and dystrobrevins

A unique arrangement of domains makes up the common region of two otherwise very different proteins - long, elegant dystrophin, and its rather dumpy distant cousin, dystrobrevin. The two work in concert, forming the core of a large membrane-bound complex in all metazoa. Like many proteins, dystrophin and dystrobrevin have diversified in the vertebrate clade, as have their binding partners, yielding specialized complexes tailored to different cellular and subcellular locations. Disruption of several components of the complex is known to result in syndromes that include progressive myopathy, sometimes combined with cognitive defects; the best known of these is Duchenne muscular dystrophy. Despite a wealth of biochemical, cell biological and genetic information, the precise role of dystrophins, dystrobrevins and their collaborators remains unclear

MAP1B Interaction with the FW Domain of the Autophagic Receptor Nbr1 Facilitates Its Association to the Microtubule Network

Selective autophagy is a process whereby specific targeted cargo proteins, aggregates, or organelles are sequestered into double-membrane-bound phagophores before fusion with the lysosome for protein degradation. It has been demonstrated that the microtubule network is important for the formation and movement of autophagosomes. Nbr1 is a selective cargo receptor that through its interaction with LC3 recruits ubiquitinated proteins for autophagic degradation. This study demonstrates an interaction between the evolutionarily conserved FW domain of Nbr1 with the microtubule-associated protein MAP1B. Upon autophagy induction, MAP1B localisation is focused into discrete vesicles with Nbr1. This colocalisation is dependent upon an intact microtubule network as depolymerisation by nocodazole treatment abolishes starvation-induced MAP1B recruitment to these vesicles. MAP1B is not recruited to autophagosomes for protein degradation as blockage of lysosomal acidification does not result in significant increased MAP1B protein levels. However, the protein levels of phosphorylated MAP1B are significantly increased upon blockage of autophagic degradation. This is the first evidence that links the ubiquitin receptor Nbr1, which shuttles ubiquitinated proteins to be degraded by autophagy, to the microtubule network

Common patterns of morbidity and multi-morbidity and their impact on health-related quality of life: evidence from a national survey.

BACKGROUND: There is limited evidence about the impact of specific patterns of multi-morbidity on health-related quality of life (HRQoL) from large samples of adult subjects. METHODS: We used data from the English General Practice Patient Survey 2011-2012. We defined multi-morbidity as the presence of two or more of 12 self-reported conditions or another (unspecified) long-term health problem. We investigated differences in HRQoL (EQ-5D scores) associated with combinations of these conditions after adjusting for age, gender, ethnicity, socio-economic deprivation and the presence of a recent illness or injury. Analyses were based on 831,537 responses from patients aged 18 years or older in 8,254 primary care practices in England. RESULTS: Of respondents, 23 % reported two or more chronic conditions (ranging from 7 % of those under 45 years of age to 51 % of those 65 years or older). Multi-morbidity was more common among women, White individuals and respondents from socio-economically deprived areas. Neurological problems, mental health problems, arthritis and long-term back problem were associated with the greatest HRQoL deficits. The presence of three or more conditions was commonly associated with greater reduction in quality of life than that implied by the sum of the differences associated with the individual conditions. The decline in quality of life associated with an additional condition in people with two and three physical conditions was less for older people than for younger people. Multi-morbidity was associated with a substantially worse HRQoL in diabetes than in other long-term conditions. With the exception of neurological conditions, the presence of a comorbid mental health problem had a more adverse effect on HRQoL than any single comorbid physical condition. CONCLUSION: Patients with multi-morbid diabetes, arthritis, neurological, or long-term mental health problems have significantly lower quality of life than other people. People with long-term health conditions require integrated mental and physical healthcare services

A novel deletion in proximal 22q associated with cardiac septal defects and microcephaly: a case report

<p>Abstract</p> <p>Background</p> <p>Proximal 22q is rich in low copy repeats (LCRs) which mediate non-allelic homologous recombination and give rise to deletions and duplications of varying size depending on which LCRs are involved.</p> <p>Methods</p> <p>A child with multiple septal defects and other congenital anomalies was investigated for genome imbalance using multiplex ligation-dependent probe amplification (MLPA) for subtelomeres and microdeletion loci, followed by array comparative genomic hybridization (CGH) using oligonucleotide arrays with 44,000 probes across the genome.</p> <p>Results</p> <p>MLPA identified a single probe deletion in the SNAP29 gene within band 22q11.21. Follow-up array CGH testing revealed a ~1.4-Mb deletion from 19,405,375 bp to 20,797,502 bp, encompassing 28 genes.</p> <p>Conclusion</p> <p>This deletion is likely to be causally associated with the proband's congenital anomalies. Previous publications describing deletions in proximal 22q have reported deletions between LCRs 1 to 4, associated with 22q11 deletion syndrome; in addition, deletions between LCRs 4 and 6 have been described associated with "distal 22q11 deletion syndrome". To our knowledge, this is the first deletion which spans LCR4 and is not apparently mediated by LCRs. Comparison of the phenotypes found in conjunction with previously reported deletions, together with the function and expression patterns of genes in the deleted region reported here, suggests that haploinsufficiency for the Crk-like (CRKL) gene may be responsible for the reported cardiac abnormalities.</p

Functional characterization of two novel 5' untranslated exons reveals a complex regulation of NOD2 protein expression

<p>Abstract</p> <p>Background</p> <p>NOD2 is an innate immune receptor for the bacterial cell wall component muramyl-dipeptide. Mutations in the leucine-rich repeat region of NOD2, which lead to an impaired recognition of muramyl-dipeptide, have been associated with Crohn disease, a human chronic inflammatory bowel disease. Tissue specific constitutive and inducible expression patterns of NOD2 have been described that result from complex regulatory events for which the molecular mechanisms are not yet fully understood.</p> <p>Results</p> <p>We have identified two novel exons of the <it>NOD2 </it>gene (designated exon 1a and 1b), which are spliced to the canonical exon 2 and constitute the 5' untranslated region of two alternative transcript isoforms (i.e. exon 1a/1b/2 and exon 1a/2). The two novel transcripts are abundantly expressed and seem to comprise the majority of NOD2 transcripts under physiological conditions. We confirm the expression of the previously known canonical first exon (designated exon 1c) of the gene in unstimulated mononuclear cells. The inclusion of the second alternative exon 1b, which harbours three short upstream open reading frames (uORFs), is downregulated upon stimulation with TNF-α or under pro-inflammatory conditions in the inflamed intestinal mucosa <it>in vivo</it>. Using the different 5' UTR splice forms fused to a firefly luciferase (LUC) reporter we demonstrate a rapamycin-sensitive inhibitory effect of the uORFs on translation efficacy.</p> <p>Conclusion</p> <p>The differential usage of two alternative promoters in the <it>NOD2 </it>gene leads to tissue-specific and context-dependent <it>NOD2 </it>transcript isoform patterns. We demonstrate for the first time that context-dependent alternative splicing is linked to uORF-mediated translational repression. The results suggest complex parallel control mechanisms that independently regulate NOD2 expression in the context of inflammatory signaling.</p

A Screen for Retrotransposed Imprinted Genes Reveals an Association between X Chromosome Homology and Maternal Germ-Line Methylation

Imprinted genes undergo epigenetic modifications during gametogenesis, which lead to transcriptional silencing of either the maternally or the paternally derived allele in the subsequent generation. Previous work has suggested an association between imprinting and the products of retrotransposition, but the nature of this link is not well defined. In the mouse, three imprinted genes have been described that originated by retrotransposition and overlap CpG islands which undergo methylation during oogenesis. Nap1l5, U2af1-rs1, and Inpp5f_v2 are likely to encode proteins and share two additional genetic properties: they are located within introns of host transcripts and are derived from parental genes on the X chromosome. Using these sequence features alone, we identified Mcts2, a novel candidate imprinted retrogene on mouse Chromosome 2. Mcts2 has been validated as imprinted by demonstrating that it is paternally expressed and undergoes promoter methylation during oogenesis. The orthologous human retrogenes NAP1L5, INPP5F_V2, and MCTS2 are also shown to be paternally expressed, thus delineating novel imprinted loci on human Chromosomes 4, 10, and 20. The striking correlation between imprinting and X chromosome provenance suggests that retrotransposed elements with homology to the X chromosome can be selectively targeted for methylation during mammalian oogenesis

A Case-by-Case Evolutionary Analysis of Four Imprinted Retrogenes

Retroposition is a widespread phenomenon resulting in the generation of new genes that are initially related to a parent gene via very high coding sequence similarity. We examine the evolutionary fate of four retrogenes generated by such an event; mouse Inpp5f_v2, Mcts2, Nap1l5, and U2af1-rs1. These genes are all subject to the epigenetic phenomenon of parental imprinting. We first provide new data on the age of these retrogene insertions. Using codon-based models of sequence evolution, we show these retrogenes have diverse evolutionary trajectories, including divergence from the parent coding sequence under positive selection pressure, purifying selection pressure maintaining parent-retrogene similarity, and neutral evolution. Examination of the expression pattern of retrogenes shows an atypical, broad pattern across multiple tissues. Protein 3D structure modeling reveals that a positively selected residue in U2af1-rs1, not shared by its parent, may influence protein conformation. Our case-by-case analysis of the evolution of four imprinted retrogenes reveals that this interesting class of imprinted genes, while similar in regulation and sequence characteristics, follow very varied evolutionary paths

Phase chaos in the anisotropic complex Ginzburg-Landau Equation

Of the various interesting solutions found in the two-dimensional complex Ginzburg-Landau equation for anisotropic systems, the phase-chaotic states show particularly novel features. They exist in a broader parameter range than in the isotropic case, and often even broader than in one dimension. They typically represent the global attractor of the system. There exist two variants of phase chaos: a quasi-one dimensional and a two-dimensional solution. The transition to defect chaos is of intermittent type.Comment: 4 pages RevTeX, 5 figures, little changes in figures and references, typos removed, accepted as Rapid Commun. in Phys. Rev.

The dystrotelin, dystrophin and dystrobrevin superfamily: new paralogues and old isoforms

BACKGROUND: Dystrophins and dystrobrevins are distantly related proteins with important but poorly understood roles in the function of metazoan muscular and neuronal tissues. Defects in them and their associated proteins cause a range of neuromuscular disorders. Members of this superfamily have been discovered in a relatively serendipitous way; we set out to compile a comprehensive description of dystrophin- and dystrobrevin-related sequences from available metazoan genome sequences, validated in representative organisms by RT-PCR, or acquired de novo from key species. RESULTS: Features of the superfamily revealed by our survey include: a) Dystrotelin, an entirely novel branch of the superfamily, present in most vertebrates examined. Dystrotelin is expressed in the central nervous system, and is a possible orthologue of Drosophila DAH. We describe the preliminary characterisation of its function, evolution and expression. b) A novel vertebrate member of the dystrobrevin family, γ-dystrobrevin, an ancient branch now extant only in fish, but probably present in our own ancestors. Like dystrophin, zebrafish γ-dystrobrevin mRNA is localised to myosepta. c) The extent of conservation of alternative splicing and alternative promoter use in the dystrophin and dystrobrevin genes; alternative splicing of dystrophin exons 73 and 78 and α-dystrobrevin exon 13 are conserved across vertebrates, as are the use of the Dp116, Dp71 and G-utrophin promoters; the Dp260 and Dp140 promoters are tetrapod innovations. d) The evolution of the unique N-terminus of DRP2 and its relationship to Dp116 and G-utrophin. e) A C-terminally truncated common ancestor of dystrophin and utrophin in cyclostomes. f) A severely restricted repertoire of dystrophin complex components in ascidians. CONCLUSION: We have refined our understanding of the evolutionary history and isoform diversity of the five previously reported vertebrate superfamily members and describe two novel members, dystrotelin and γ-dystrobrevin. Dystrotelins, dystrophins and dystrobrevins are roughly equally related to each other. Vertebrates therefore have a repertoire of seven superfamily members (three dystrophins, three dystrobevins, and one dystrotelin), with one lost in tetrapods. Most invertebrates studied have one member from each branch. Although the basic shared function which is implied by the common architecture of these distantly related proteins remains unclear, it clearly permeates metazoan biology

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care