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The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9.

Am J Physiol Lung Cell Mol Physiol. 2017 Jun 01;312(6):L912-L925

Authors: Bertrand CA, Mitra S, Mishra SK, Wang X, Zhao Y, Pilewski JM, Madden DR, Frizzell RA

Abstract
Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it is unclear which PDZ-domain protein(s) interact with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9. However, constitutive anion secretion is absent in HBE from CF donors. We examined whether changes in SLC26A9 constitutive activity could be attributed to a loss of CFTR trafficking, and what role PDZ interactions played. HEK293 coexpressing SLC26A9 with the trafficking mutant F508del CFTR exhibited a significant reduction in constitutive current compared with cells coexpressing SLC26A9 and wt CFTR. We found that SLC26A9 exhibits complex glycosylation when coexpressed with F508del CFTR, but its expression at the plasma membrane is decreased. SLC26A9 interacted with both NHERF-1 and CAL, and its interaction with both significantly increased with coexpression of wt CFTR. However, coexpression with F508del CFTR only increased SLC26A9's interaction with CAL. Mutation of SLC26A9's PDZ motif decreased this association with CAL, and restored its constitutive activity. Correcting aberrant F508del CFTR trafficking in CF HBE with corrector VX-809 also restored SLC26A9 activity. We conclude that when SLC26A9 is coexpressed with F508del CFTR, its trafficking defect leads to a PDZ motif-sensitive intracellular retention of SLC26A9.

PMID: 28360110 [PubMed - indexed for MEDLINE]

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How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

Am J Respir Crit Care Med. 2017 Jul 15;196(2):139-149

Authors: Beeh KM, Burgel PR, Franssen FME, Lopez-Campos JL, Loukides S, Hurst JR, Fležar M, Ulrik CS, Di Marco F, Stolz D, Valipour A, Casserly B, Ställberg B, Kostikas K, Wedzicha JA

Abstract
Decreasing the frequency and severity of exacerbations is one of the main goals of treatment for patients with chronic obstructive pulmonary disease. Several studies have documented that long-acting bronchodilators can reduce exacerbation rate and/or severity, and others have shown that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroid combinations in patients at low and high risk for these events. In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single long-acting bronchodilators or LABA/inhaled corticosteroids in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary clearance, and symptom severity may all contribute to decreasing exacerbations. Although preclinical studies suggest LABAs and LAMAs have antiinflammatory effects, such effects have not been demonstrated yet in patients with chronic obstructive pulmonary disease.

PMID: 27922741 [PubMed - indexed for MEDLINE]

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Clinical Genomics in Inflammatory Bowel Disease.

Trends Genet. 2017 Jul 26;:

Authors: Uhlig HH, Muise AM

Abstract
Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from 'orphan disease' research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine. IBD is nevertheless a challenging example for genomic medicine because the overall fraction of patients with Mendelian defects is low, the number of potential candidate genes is high, and interventional evidence is still emerging. We discuss requirements and prospects of explanatory and predictive clinical genomics in IBD.

PMID: 28755896 [PubMed - as supplied by publisher]

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Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.

Am J Hum Genet. 2017 Jun 01;100(6):978-984

Authors: Boyden LM, Vincent NG, Zhou J, Hu R, Craiglow BG, Bayliss SJ, Rosman IS, Lucky AW, Diaz LA, Goldsmith LA, Paller AS, Lifton RP, Baserga SJ, Choate KA

Abstract
The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

PMID: 28575652 [PubMed - indexed for MEDLINE]

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Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

Am J Hum Genet. 2017 Jun 01;100(6):926-939

Authors: Heinz L, Kim GJ, Marrakchi S, Christiansen J, Turki H, Rauschendorf MA, Lathrop M, Hausser I, Zimmer AD, Fischer J

Abstract
Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism.

PMID: 28575648 [PubMed - indexed for MEDLINE]

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Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella.

Am J Hum Genet. 2017 Jun 01;100(6):854-864

Authors: Tang S, Wang X, Li W, Yang X, Li Z, Liu W, Li C, Zhu Z, Wang L, Wang J, Zhang L, Sun X, Zhi E, Wang H, Li H, Jin L, Luo Y, Wang J, Yang S, Zhang F

Abstract
Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAF-associated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia- and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43- and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

PMID: 28552195 [PubMed - indexed for MEDLINE]

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Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.

Blood. 2016 Sep 29;128(13):1735-44

Authors: Weinhold N, Ashby C, Rasche L, Chavan SS, Stein C, Stephens OW, Tytarenko R, Bauer MA, Meissner T, Deshpande S, Patel PH, Buzder T, Molnar G, Peterson EA, van Rhee F, Zangari M, Thanendrarajan S, Schinke C, Tian E, Epstein J, Barlogie B, Davies FE, Heuck CJ, Walker BA, Morgan GJ

Abstract
To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.

PMID: 27516441 [PubMed - indexed for MEDLINE]

Funding Opportunity PA-17-443 from the NIH Guide for Grants and Contracts. The purpose of this FOA is to support investigator-initiated R01 applications that will inform our understanding of the typical and atypical patterns of language and literacy development of dual language learners (DLLs) in the United States. Applicants are encouraged to take advantage of advances in the language sciences and related fields to identify and clarify specific cognitive, linguistic, neurobiological, and sociocultural factors associated with normal and impaired language and literacy acquisition in young DLL populations.

Funding Opportunity PA-17-448 from the NIH Guide for Grants and Contracts. The purpose of this FOA is to support investigator-initiated R21 applications that will inform our understanding of the typical and atypical patterns of language and literacy development of dual language learners (DLLs) in the United States. Applicants are encouraged to take advantage of advances in the language sciences and related fields to identify and clarify specific cognitive, linguistic, neurobiological, and sociocultural factors associated with normal and impaired language and literacy acquisition in young DLL populations.

Notice NOT-DA-17-050 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-447 from the NIH Guide for Grants and Contracts. The reproducibility and comparability of dietary supplement research is enhanced through rigorous analytical characterization of key experimental materials. The publication of analytical methods which have been thoroughly validated for specific, precise, accurate, and sensitive quantitative determination of chemical constituents of dietary supplements therefore makes critical contributions to the rigor and reproducibility of biomedical research. This FOA will build on existing NIH awards to support the performance and publication of formal single-laboratory validation studies of relevant quantitative analytical methods. The methods proposed for validation must be used to identify and quantify chemical constituents (active or marker chemical compounds, adulterants, contaminants) or metabolites thereof in experimental reagents, raw materials, and/or clinical specimens (for example urine or plasma samples). Methods must have been developed or utilized in fulfillment of the active parent grants specific aims. Candidate constituents for quantitative method validation studies may include (but are not limited to): phytochemicals, nutrients, and potentially deleterious substances such as pesticides and mycotoxins. Multi-laboratory validation studies will not be supported through this FOA.

Funding Opportunity RFA-HL-18-024 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to stimulate research on cardiovascular and pulmonary physiologic and health effects of electronic cigarette (e-cigarette) exposure. This FOA invites applications addressing the effects of e-cigarettes on the cardiovascular and pulmonary systems, alone or in combination. Studies involving clinical populations, animal models and/or cell preparations would all be considered responsive. Research may examine the effects of the whole e-cigarette aerosol or of individual components or constituents. Research may also examine where aerosols, components, or constituents deposit in the airways and resulting heart and/or lung consequences.

Notice NOT-CA-17-075 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-076 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-444 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Research Project Grant (R01) applications that propose to study the ethical, legal and social implications (ELSI) of human genome research. Applications may propose studies using either single or mixed methods. Proposed approaches may include but are not limited to data-generating qualitative and quantitative approaches, legal, economic and normative analyses, and other types of analytical and conceptual research methodologies, such as those involving the direct engagement of stakeholders.

Funding Opportunity PA-17-445 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Small Research Grant (R03) applications to study the ethical, legal and social implications (ELSI) of human genome research. These applications should be for small, self-contained research projects, such as those that involve single investigators. Of particular interest are projects that propose normative or conceptual analyses, including focused legal, economic, philosophical, anthropological, or historical analyses of new or emerging issues. This mechanism can also be used for the collection of preliminary data and the secondary analysis of existing data.

Funding Opportunity PA-17-446 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites Exploratory/Developmental Research Grant (R21) applications that propose to study the ethical, legal and social implications (ELSI) of human genome research. These applications should propose single or mixed methods studies that break new ground, extend previous discoveries in new directions or develop preliminary data in preparation for larger studies. Of particular interest are studies that explore the implications of new or emerging genomic technologies or novel uses of genomic information.

Funding Opportunity RFA-RM-17-011 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) addresses the need for a robust National Metabolomics Data Repository to store, and make publicly available, raw and processed metabolomic data generated by large NIH programs, individual research grants, and other biomedical research groups. Data, associated metadata, and the essential tools critical for accessing the key information will be housed in a cloud computing environment accessible for searching and reanalysis by the biomedical research community. The Metabolomics Data Repository and Coordination Center (DRCC), created in Stage I of the Common Fund Metabolomics Program, has begun to address this need. In the transition to a National Metabolomics Data Repository, the successful applicant is expected to continue and enhance the current technical capabilities of the Data Repository and create a governance structure that engages the wider metabolomics community to guide the repositorys efforts toward continual technical improvement and expansion and policy development for data deposition, access, and citation.

Funding Opportunity RFA-RM-17-012 from the NIH Guide for Grants and Contracts. The goal of this cooperative agreement Funding Opportunity Announcement (FOA) is to address key challenges in analyzing and interpreting metabolomics data by developing novel tools to facilitate metabolomics data analysis and interpretation. Specifically, successful awardees will develop new or enhanced computational approaches or tools that facilitate metabolomics data analysis, interpretation, and integration. Generalizable, scalable, and portable solutions appropriate for scientists with limited expertise in informatics are particularly encouraged. Projects are not intended to supplement ongoing metabolomics analyses, but to provide tools for broader use by the biomedical research community.

Funding Opportunity RFA-RM-17-013 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications to establish Compound Identification Development Cores (CIDC) to develop innovative approaches to enhance compound identification of the most significant, biomedically-relevant unknown metabolites. The ultimate goal of this FOA is to expand the repertoire of biologically relevant compounds that can be quickly and inexpensively identified in high throughput metabolomics experiments. An interdisciplinary approach and partnership among metabolomics experts, biomedical researchers, chemists, and computational experts will be integral to the success of this goal, and advances made through this initiative are expected to be catalytic to the field.