Notice NOT-DA-17-048 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-HG-17-011 from the NIH Guide for Grants and Contracts. The scope of this FOA is to establish the NHGRI Genomic Data Science Analysis, Visualization, Informatics Lab-space ("AnVIL") in support of genomic research. The AnVIL aims to create an interoperable resource for the research community by co-locating data, storage and computing infrastructure with commonly used services and tools for analyzing and sharing data. The AnVIL will further advance research by leveraging a cloud-based infrastructure to facilitate genomic data access by the broad scientific community, integration and computing on and across large datasets generated by NHGRI programs, or programs funded by others in support of human genomics research.

Genotypic diversity and phenotypic traits of Streptococcus mutans isolates and their relation to severity of early childhood caries.

BMC Oral Health. 2017 Jul 14;17(1):115

Authors: Valdez RMA, Duque C, Caiaffa KS, Dos Santos VR, Loesch MLA, Colombo NH, Arthur RA, Negrini TC, Boriollo MFG, Delbem ACB

Abstract
BACKGROUND: Early childhood caries (ECC) is an aggressive condition that can affect teeth of young children. This study aimed to evaluate genotypic diversity and phenotypic traits of S. mutans isolated from dental biofilms of children with different caries status in comparison with caries free (CF) children.
METHODS: Streptococcus mutans strains were isolated from supragingival biofilm samples of CF, ECC and severe-ECC (S-ECC) children and genotyped by arbitrary-primer polymerase chain reaction - AP-PCR. S. mutans genotypes were tested for their ability to reduce the suspension pH through glycolysis, to tolerate extreme acid challenge and by their ability to form biofilm. Response variables were analyzed by ANOVA/Tukey or Kruskal-Wallis/Mann-Whitney tests at a 5% of significance.
RESULTS: There was an increase in the prevalence of Streptococcus mutans in biofilms with the severity of dental caries. No differences in genotypic diversity and in acidogenicity of genotypes were found among CF, ECC and S-ECC children. S mutans strains with genotypes more characteristic for ECC and S-ECC children formed more biofilms than those identified in CF children. The strains isolated from S-ECC children were highly acid tolerant.
CONCLUSION: Although S. mutans genotypic diversity was similar among the groups of children, phenotypic traits of S. mutans, especially the acid tolerance response, could explain the severity of early childhood caries.

PMID: 28709424 [PubMed - in process]

Chitosan Membranes application on the Prostatic Neurovascular Bundles following Robot-assisted Radical Prostatectomy: a phase II study.

BJU Int. 2017 Jul 15;:

Authors: Porpiglia F, Bertolo R, Fiori C, Manfredi M, De Cillis S, Geuna S

Abstract
OBJECTIVE: To evaluate the feasibility and the safety of the application of chitosan membranes on the neuro-vascular bundles after nerve-sparing Robot-Assisted Radical Prostatectomy (RARP). The secondary aim of the study was to report preliminary data and more particularly potency recovery data.
MATERIALS AND METHODS: Single-center, single-arm prospective study. Enrolment from July 2015 to September 2016 of all patients with localized prostate cancer scheduled for RARP with IIEF-5 score > 17 after San Luigi Gonzaga Hospital Ethics Committee (Orbassano) approval (80/2015) and patient's acceptance. All patients underwent nerve-sparing RARP with application of Chitosan Membranes on the neuro-vascular bundles. Demographics, peri-operative, postoperative data and complications were evaluated. Potency recovery data were particularly evaluated. Specifically for the purpose of the study, any referred sign/symptom of local allergy/intolerance to the chitosan membranes was recorded and evaluated.
RESULTS: Hundred-forty patients underwent nerve-sparing RARP with chitosan membranes application on the neuro-vascular bundles. The application was easy in almost all the cases and did not compromise the safety of the procedure. None of the patients reported signs of intolerance/allergy attributable to the membranes.
CONCLUSION: In our experience chitosan membranes application on the neuro-vascular bundles after nerve-sparing RARP was feasible and safe, without compromising the length, the difficulty and the complications rate of the "standard" procedure. No patients experienced signs of intolerance/allergy attributable to the membranes. Potency recovery data were encouraging. Comparative cohort would have added value to the study. The present paper was performed pre-CE mark achievement. This article is protected by copyright. All rights reserved.

PMID: 28710845 [PubMed - as supplied by publisher]

Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter.

Sci Rep. 2017 Jul 14;7(1):5399

Authors: Ma S, Cheng MH, Guthrie DA, Newman AH, Bahar I, Sorkin A

Abstract
Dopamine transporter (DAT) has been shown to accumulate in filopodia in neurons and non-neuronal cells. To examine the mechanisms of DAT filopodial targeting, we used quantitative live-cell fluorescence microscopy, and compared the effects of the DAT inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two non-functional DAT mutants, R60A and W63A, that do not accumulate in filopodia. W63A did not bind JHC1-64, whereas R60A did, although less efficiently compared to the wild-type DAT. Molecular dynamics simulations predicted that R60A preferentially assumes an outward-facing (OF) conformation through compensatory intracellular salt bridge formation, which in turn favors binding of cocaine. Imaging analysis showed that JHC1-64-bound R60A mutant predominantly localized in filopodia, whereas free R60A molecules were evenly distributed within the plasma membrane. Cocaine binding significantly increased the density of R60A, but not that of W63A, in filopodia. Further, zinc binding, known to stabilize the OF state, also increased R60A concentration in filopodia. Finally, amphetamine, that is thought to disrupt DAT OF conformation, reduced the concentration of wild-type DAT in filopodia. Altogether, these data indicate that OF conformation is required for the efficient targeting of DAT to, and accumulation in, filopodia.

PMID: 28710426 [PubMed - in process]

Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile and transcriptional landscape.

Clin Cancer Res. 2017 Jul 14;:

Authors: Wang Z, Kim TB, Peng B, Karam JA, Creighton CJ, Joon AY, Kawakami F, Trevisan P, Jonasch E, Chow CW, Rodriguez-Canales J, Tamboli P, Tannir NM, Wood CG, Monzon FA, Baggerly KA, Varella-Garcia M, Czerniak B, Wistuba II, Mills GB, Shaw K, Chen K, Sircar K

Abstract
PURPOSE: Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.<br /><br />Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of non-sarcomatoid RCC (RCC). We evaluated whole exome sequencing, single nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n=65) and RCC (n=598) across different parent RCC subtypes, including clear cell RCC, papillary RCC, and chromophobe RCC subtypes.  <br /><br />Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes.  The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer related genes, despite a higher mutational burden in S-.  Notably, sarcomatoid clear cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared to clear cell RCC (ccRCC).  A two-hit loss involving VHL predicted for ccRCC and a better prognosis whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.  <br /><br />Conclusions: Sarcomatoid RCC segregates by parent subtype and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles.  These features prompt a more precise molecular classification of RCC with diagnostic, prognostic, and therapeutic implications.

PMID: 28710314 [PubMed - as supplied by publisher]

Phylogenetic Quantification of Intratumor Heterogeneity.

Cold Spring Harb Perspect Med. 2017 Jul 14;:

Authors: Watkins TBK, Schwarz RF

Abstract
As sequencing efforts continue to reveal the extent of the intratumor heterogeneity (ITH) present in human cancers, the importance of evolutionary studies attempting to trace its etiology has increased. Sequencing multiple samples or tumor regions from the same patient has become affordable and is an effective way of tracing these evolutionary pathways, understanding selection, and detecting clonal expansions in ways impractical with single samples alone. In this article, we discuss and show the benefits of such multisample studies. We describe how multiple samples can guide tree inference through accurate phasing of germline variants and copy-number profiles. We show their relevance in detecting clonal expansions and deriving summary statistics quantifying the overall degree of ITH, and discuss how the relationship of metastatic clades might give us insight into the dominant mode of cancer progression. We further outline how multisample studies might help us better understand selective processes acting on cancer genomes and help to detect neutral evolution and mutator phenotypes.

PMID: 28710259 [PubMed - as supplied by publisher]

The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia.

EMBO Rep. 2017 Jul 14;:

Authors: Kohli P, Höhne M, Jüngst C, Bertsch S, Ebert LK, Schauss AC, Benzing T, Rinschen MM, Schermer B

Abstract
Primary cilia are sensory, antennae-like organelles present on the surface of many cell types. They have been involved in a variety of diseases collectively termed ciliopathies. As cilia are essential regulators of cell signaling, the composition of the ciliary membrane needs to be strictly regulated. To understand regulatory processes at the ciliary membrane, we report the targeting of a genetically engineered enzyme specifically to the ciliary membrane to allow biotinylation and identification of the membrane-associated proteome. Bioinformatic analysis of the comprehensive dataset reveals high-stoichiometric presence of actin-binding proteins inside the cilium. Immunofluorescence stainings and complementary interaction proteomic analyses confirm these findings. Depolymerization of branched F-actin causes further enrichment of the actin-binding and actin-related proteins in cilia, including Myosin 5a (Myo5a). Interestingly, Myo5a knockout decreases ciliation while enhanced levels of Myo5a are observed in cilia upon induction of ciliary disassembly. In summary, we present a novel approach to investigate dynamics of the ciliary membrane proteome in mammalian cells and identify actin-binding proteins as mechanosensitive components of cilia that might have important functions in cilia membrane dynamics.

PMID: 28710093 [PubMed - as supplied by publisher]

Create, run, share, publish, and reference your LC-MS, FIA-MS, GC-MS, and NMR data analysis workflows with Workflow4Metabolomics 3.0, the Galaxy online infrastructure for metabolomics.

Int J Biochem Cell Biol. 2017 Jul 11;:

Authors: Guitton Y, Tremblay-Franco M, Le Corguillé G, Martin JF, Pétéra M, Roger-Mele P, Delabrière A, Goulitquer S, Monsoor M, Duperier C, Canlet C, Servien R, Tardivel P, Caron C, Giacomoni F, Thévenot EA

Abstract
Metabolomics is a key approach in modern functional genomics and systems biology. Due to the complexity of metabolomics data, the variety of experimental designs, and the variety of existing bioinformatics tools, providing experimenters with a simple and efficient resource to conduct comprehensive and rigorous analysis of their data is of utmost importance. In 2014, we launched the Workflow4Metabolomics (W4M; http://workflow4metabolomics.org) online infrastructure for metabolomics built on the Galaxy environment, which offers user-friendly features to build and run data analysis workflows including preprocessing, statistical analysis, and annotation steps. Here we present the new W4M 3.0 release, which contains twice as many tools as the first version, and provides two features which are, to our knowledge, unique among online resources. First, data from the four major metabolomics technologies (i.e., LC-MS, FIA-MS, GC-MS, and NMR) can be analyzed on a single platform. By using three studies in human physiology, alga evolution, and animal toxicology, we demonstrate how the 40 available tools can be easily combined to address biological issues. Second, the full analysis (including the workflow, the parameter values, the input data and output results) can be referenced with a permanent digital object identifier (DOI). Publication of data analyses is of major importance for robust and reproducible science. Furthermore, the publicly shared workflows are of high-value for e-learning and training. The Workflow4Metabolomics 3.0 e-infrastructure thus not only offers a unique online environment for analysis of data from the main metabolomics technologies, but it is also the first reference repository for metabolomics workflows.

PMID: 28710041 [PubMed - as supplied by publisher]

Local network component analysis for quantifying transcription factor activities.

Methods. 2017 Jul 11;:

Authors: Shi Q, Zhang C, Guo W, Zeng T, Lu L, Jiang Z, Wang Z, Liu J, Chen L

Abstract
Transcription factors (TFs) could regulate physiological transitions or determine stable phenotypic diversity. The accurate estimation on TF regulatory signals or functional activities is of great significance to guide biological experiments or elucidate molecular mechanisms, but still remains challenging. Traditional methods identify TF regulatory signals at the population level, which masks heterogeneous regulation mechanisms in individuals or subgroups, thus resulting in inaccurate analyses. Here, we propose a novel computational framework, namely Local Network Component Analysis (LNCA), to exploit data heterogeneity and automatically quantify accurate transcription factor activity (TFA) in practical terms, through integrating the partitioned expression sets (i.e., local information) and prior TF-gene regulatory knowledge. Specifically, LNCA adopts an adaptive optimization strategy, which evaluates the local similarities of regulation controls and corrects biases during data integration, to construct the TFA landscape. In particular, we first numerically demonstrate the effectiveness of LNCA for the simulated data sets, compared with traditional methods, such as FastNCA, ROBNCA and NINCA. Then, we apply our model to two real data sets with implicit temporal or spatial regulation variations. The results show that LNCA not only recognizes the periodic mode along the S. cerevisiae cell cycle process, but also substantially outperforms over other methods in terms of accuracy and consistency. In addition, the cross-validation study for glioblastomas multiforme (GBM) indicates that the TFAs, identified by LNCA, can better distinguish clinically distinct tumor groups than the expression values of the corresponding TFs, thus opening a new way to classify tumor subtypes and also providing a novel insight into cancer heterogeneity.
AVAILABILITY: LNCA was implemented as a Matlab package, which is available at http://www.sysbio.ac.cn/cb/chenlab/images/LNCApackage_0.1.rar.

PMID: 28710010 [PubMed - as supplied by publisher]

mRNA interactome capture in mammalian cells.

Methods. 2017 Jul 11;:

Authors: Kastelic N, Landthaler M

Abstract
Throughout their entire life cycle, mRNAs are associated with RNA-binding proteins (RBPs), forming ribonucleoprotein (RNP) complexes with highly dynamic compositions. Their interplay is one key to control gene regulatory mechanisms from mRNA synthesis to decay. To assay the global scope of RNA-protein interactions, we and others have published a method combining crosslinking with highly stringent oligo(dT) affinity purification to enrich proteins associated with polyadenylated RNA (poly(A)+ RNA). Identification of the poly(A)+ RNA-bound proteome (also: mRNA interactome capture) has by now been applied to a diversity of cell lines and model organisms, uncovering comprehensive repertoires of RBPs and hundreds of novel RBP candidates. In addition to determining the RBP catalog in a given biological system, mRNA interactome capture allows the examination of changes in protein-mRNA interactions in response to internal and external stimuli, altered cellular programs and disease.

PMID: 28710009 [PubMed - as supplied by publisher]

Ganoderma triterpenes retard renal cyst development by downregulating Ras/MAPK signaling and promoting cell differentiation.

Kidney Int. 2017 Jul 11;:

Authors: Su L, Liu L, Jia Y, Lei L, Liu J, Zhu S, Zhou H, Chen R, Lu HAJ, Yang B

Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by the progressive development of renal cysts with further need for effective therapy. Here our aim was to investigate the effect of Ganoderma triterpenes (GT) on the development of kidney cysts. Importantly, GT attenuated cyst development in two mouse models of ADPKD with phenotypes of severe cystic kidney disease. Assays for tubulogenesis showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signaling pathways involved in the pathogenesis of PKD was further investigated by immune blotting. This showed that GT specifically downregulated the activation of the Ras/MAPK signaling pathway both in vitro and in vivo without detectable effect on the mTOR pathway. This mechanism may be involved in GT downregulating intracellular cAMP levels. Screening of 15 monomers purified from GT for their effects on cyst development indicated that CBLZ-7 (ethyl ganoderate C2) had a potent inhibitory effect on cyst development in vitro. Additionally, like GT, CBLZ-7 was able to downregulate forskolin-induced activation of the Ras/MAPK pathway. Thus, GT and its purified monomer CBLZ-7 may be potential therapeutic regents for treating ADPKD.

PMID: 28709639 [PubMed - as supplied by publisher]

Fluctuation relations between hierarchical kinetically equivalent networks with Arrhenius-type transitions and their roles in systems and structural biology.

Phys Rev E. 2017 Jun;95(6-1):062401

Authors: Deng DM, Lu YT, Chang CH

Abstract
The legality of using simple kinetic schemes to determine the stochastic properties of a complex system depends on whether the fluctuations generated from hierarchical equivalent schemes are consistent with one another. To analyze this consistency, we perform lumping processes on the stochastic differential equations and the generalized fluctuation-dissipation theorem and apply them to networks with the frequently encountered Arrhenius-type transition rates. The explicit Langevin force derived from those networks enables us to calculate the state fluctuations caused by the intrinsic and extrinsic noises on the free energy surface and deduce their relations between kinetically equivalent networks. In addition to its applicability to wide classes of network related systems, such as those in structural and systems biology, the result sheds light on the fluctuation relations for general physical variables in Keizer's canonical theory.

PMID: 28709185 [PubMed - in process]

Elfamycins: Inhibitors of Elongation Factor-Tu.

Mol Microbiol. 2017 Jul 15;:

Authors: Prezioso SM, Brown NE, Goldberg JB

Abstract
Elfamycins are a relatively understudied group of antibiotics that target the essential process of translation through impairment of EF-Tu function. For the most part, the utility of these compounds has been as laboratory tools for the study of EF-Tu and the ribosome, as their poor pharmacokinetic profile and solubility has prevented implementation as therapeutic agents. However, due to the slowing of the antibiotic pipeline and the rapid emergence of resistance to approved antibiotics, this group is being reconsidered. Some researchers are using screens for novel naturally produced variants, while others are making directed, systematic chemical improvements on publically disclosed compounds. As an example of the latter approach, a GE2270 A derivative, LFF571, has completed phase 2 clinical trials, thus demonstrating the potential for elfamycins to become more prominent antibiotics in the future. This article is protected by copyright. All rights reserved.

PMID: 28710887 [PubMed - as supplied by publisher]

Effects of inhaled hypertonic (7%) saline on lung function test in preschool children with cystic fibrosis: results of a crossover, randomized clinical trial.

Ital J Pediatr. 2017 Jul 15;43(1):60

Authors: Nenna R, Midulla F, Lambiase C, De Castro G, Zicari AM, Indinnimeo L, Cimino G, Troiani P, Quattrucci S, Tancredi G

Abstract
BACKGROUND: This crossover, randomized, double-blind study (conducted over a 32-week period) was performed to determine, in clinically stable Cystic fibrosis (CF) preschool children: the effects of 7% inhaled hypertonic saline on spirometry and interrupter resistance technique (Rint), and the possible side effects.
METHODS: Twelve CF children (6M, mean age ± SD: 5.7 ± 0.8 yrs) were enrolled and randomly assigned to receive hypertonic saline (HS-4 ml 7% sodium chloride), or normal saline (NS-0.9% sodium chloride) twice a day. After a 16 weeks period, therapy was exchanged to allow all the patients enrolled in the study to carry out both treatments. Monitoring visits, spirometry (COSMED Quark PFT4 ergo) and Rint were scheduled at 0,4,16,20,32 weeks. At T0, spirometric measurements and Rint were performed immediately before and 30 min after the inhalation therapy. Salbutamol (400 mcg) was administered before the drug at each visit.
RESULTS: After a 16-weeks treatment with HS an improvement of FVC (p = 0.02) and a favorable trend of FEV1 were registered. A worsening of FEV1 (p < 0.0001) and of FEF25-75 (p = 0.019) were found in NS group. No differences were found in expiratory and inspiratory Rint in both groups. No serious adverse events occurred.
CONCLUSIONS: Seven percent hypertonic saline therapy proved to be a useful and safe treatment in young CF children with clinically stable conditions.
TRIAL REGISTRATION: ISRCTN12345678 .

PMID: 28709466 [PubMed - in process]

Genetic and epigenetic drivers of neuroendocrine tumors (NET).

Endocr Relat Cancer. 2017 Jul 14;:

Authors: Di Domenico A, Wiedmer T, Marinoni I, Perren A

Abstract
Neuroendocrine tumors (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumors. The molecular characterization and the clinical classification of these tumors have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodeling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from-omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

PMID: 28710117 [PubMed - as supplied by publisher]

A Missense Mutation in the Extracellular Domain of αENaC Causes Liddle Syndrome.

J Am Soc Nephrol. 2017 Jul 14;:

Authors: Salih M, Gautschi I, van Bemmelen MX, Di Benedetto M, Brooks AS, Lugtenberg D, Schild L, Hoorn EJ

Abstract
Liddle syndrome is an autosomal dominant form of hypokalemic hypertension due to mutations in the β- or γ-subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle syndrome due to a mutation in αENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding β- or γENaC. Exome sequencing revealed a heterozygous, nonconservative T>C single-nucleotide mutation in αENaC that substituted Cys479 with Arg (C479R). C479 is a highly conserved residue in the extracellular domain of ENaC and likely involved in a disulfide bridge with the partner cysteine C394. In oocytes, the C479R and C394S mutations resulted in similar twofold increases in amiloride-sensitive ENaC current. Quantification of mature cleaved αENaC in membrane fractions showed that the number of channels did not increase with these mutations. Trypsin, which increases open probability of the channel by proteolytic cleavage, resulted in significantly higher currents in the wild type than in C479R or C394S mutants. In summary, a mutation in the extracellular domain of αENaC causes Liddle syndrome by increasing intrinsic channel activity. This mechanism differs from that of the β- and γ-mutations, which result in an increase in channel density at the cell surface. This mutation may explain other cases of patients with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension.

PMID: 28710092 [PubMed - as supplied by publisher]

Steroid sulfatase and filaggrin mutations in a boy with severe ichthyosis, elevated serum IgE level and moyamoya syndrome.

Gene. 2017 Jul 11;:

Authors: Zhang Q, Si N, Liu Y, Zhang D, Wang R, Zhang Y, Wang S, Liu X, Deng X, Ma Y, Ge P, Zhao J, Zhang X

Abstract
X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema. We report a case of a 6-year-old boy who presented with unusually severe XLI, an increased serum immunoglobulin E level (2120IU/ml) and moyamoya angiopathy. Whole-exome sequencing identified a gross deletion encompassing the STS in Xp22.31 and the p.K4022X FLG mutation. The deletion is at least 1.6Mb in size in the proband, based on real-time quantitative polymerase chain reaction results. No other genetic mutations related to ichthyosis, moyamoya or hyper-immunoglobulin E syndrome were detected. Furthermore, his mother's brothers suffered from mild XLI and only had a deletion encompassing the STS. Additionally, his father and older sister suffered from mild ichthyosis vulgaris and had the p.K4022X FLG mutation. We report the first case of XLI with concurrent moyamoya syndrome. Moreover, an IgE-mediated immune response may have triggered the moyamoya signaling cascade in this patient with ichthyosis. Furthermore, our study strengthens the hypothesis that filaggrin defects can synergize with an STS deficiency to exacerbate the ichthyosis phenotype in an ethnically diverse population.

PMID: 28710038 [PubMed - as supplied by publisher]

Screening for TMEM230 mutations in young-onset Parkinson's disease.

Neurobiol Aging. 2017 Jun 24;:

Authors: Ma D, Foo JN, Yulin Ng E, Zhao Y, Liu JJ, Tan EK

Abstract
TMEM230 gene mutations have been reported to be linked with Parkinson's disease (PD) recently. To investigate the prevalence of this gene in southeastern Chinese patients with PD, whole exome sequencing was performed in young-onset and familial PD patients and healthy controls in our Asian population. One heterozygous missense p.Phe121Ser mutation was detected in a healthy 76-year-old control subject and no other TMEM230 mutations were found in PD patients and controls. These data suggest that TMEM230 mutation might be a rare cause of Chinese familial and sporadic PD patients and a larger sample size will be needed to evaluate the association of TMEM230 polymorphic variants with PD.

PMID: 28709721 [PubMed - as supplied by publisher]

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

Neurobiol Aging. 2017 Jun 20;:

Authors: Pang SY, Hsu JS, Teo KC, Li Y, Kung MHW, Cheah KSE, Chan D, Cheung KMC, Li M, Sham PC, Ho SL

Abstract
Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS.

PMID: 28709720 [PubMed - as supplied by publisher]