@article {439, title = {Integrated gene set analysis for microRNA studies.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 09 15}, pages = {2809-16}, abstract = {

MOTIVATION: Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.

RESULTS: We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.

AVAILABILITY AND IMPLEMENTATION: The proposed methodology was implemented in the Bioconductor library mdgsa http://bioconductor.org/packages/mdgsa For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna

CONTACT: : david.montaner@gmail.com

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Computational Biology, Gene Expression Profiling, Gene ontology, Gene Regulatory Networks, High-Throughput Nucleotide Sequencing, Humans, MicroRNAs, Neoplasms, Reproducibility of Results}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btw334}, author = {Garcia-Garcia, Francisco and Panadero, Joaquin and Dopazo, Joaquin and Montaner, David} } @article {450, title = {Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {24-31}, abstract = {

Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.

}, keywords = {Adolescent, Antigens, CD, Child, Child, Preschool, Craniosynostoses, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Intellectual Disability, Male, mutation, Pedigree, Phenotype, Prognosis, Repressor Proteins}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37418}, author = {Urreizti, Roser and Roca-Ayats, Neus and Trepat, Judith and Garcia-Garcia, Francisco and Alem{\'a}n, Alejandro and Orteschi, Daniela and Marangi, Giuseppe and Neri, Giovanni and Opitz, John M and Dopazo, Joaquin and Cormand, Bru and Vilageliu, Llu{\"\i}sa and Balcells, Susana and Grinberg, Daniel} } @article {463, title = {Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4037-48}, abstract = {

Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.

}, keywords = {Amino Acid Sequence, Animals, Chlorocebus aethiops, Chromosome Mapping, COS Cells, DNA-Binding Proteins, Exome, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Molecular Sequence Data, Mutant Proteins, Pedigree, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Transcription Factors}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alejandro and Fernandez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W J and Cuenca, Nicolas and Ayuso, Carmen} }