Search results for " splicing"
showing 10 items of 226 documents
HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans
2019
The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth ind…
Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD
2007
B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-kappaB (NF-kappaB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8) mice), which is a deubiquitinating enzyme that is integral to NF-kappaB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occur…
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
2013
Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promot…
Transcription of human neuronal nitric oxide synthase mRNAs derived from different first exons is partly controlled by exon 1-specific promoter seque…
2006
AbstractThe human neuronal nitric oxide synthase (NOS1) gene is subject to extensive splicing. A total of 12 NOS1 mRNA species have been identified. They differ in their 5′ ends and are derived from 12 different first exons (termed exons 1a to 1l). Various cell lines whose NOS1 first exon expression patterns were representative of human brain, skin, and skeletal muscle were identified. These included A673 neuroepithelioma cells, SK-N-MC neuroblastoma cells, HaCaT keratinocyte-like cells, and C2C12 myocyte-like cells. In these cell lines, correlations were found between the exon 1 variants preferentially expressed and the promoter activities of their cognate 5′ flanking sequences. These data…
Transcription of different exons 1 of the human neuronal nitric oxide synthase gene is dynamically regulated in a cell- and stimulus-specific manner.
2003
An extensive screening of the human neuronal nitric oxide synthase (nNOS) mRNAs in various human tissues and cell lines unraveled an extreme complexity in the transcription of this gene. Using 5'rapid amplification of cDNA ends (5'-RACE), ten different exons 1 (named 1a-1l) were identified. They were spliced in a cell-specific manner to a common exon 2, which bears the translational start site. Three first exons (1 d, 1g and 1f) were used predominantly for the transcription of the nNOS gene (146 out of 197 5'-RACE clones contained these exons). Exon 1 k was found alone, but in many instances was interposed between exons 1 b, 1d, 1g, 1 i or 1j and the common exon 2. In addition to the cell-s…
One gene, two transcripts: isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary …
1994
A cDNA library was prepared from peripheral blood lymphocytes of an autoimmune patient with primary Sjögrens' syndrome. The cDNA library was screened with the patients own autoimmune serum being monospecific for the nuclear autoantigen La/SS-B. Thereby an alternative type of La mRNA was identified that differed from the known La mRNA due to an exchange of the exon 1. Sequencing of the genomic region between the exons 1 and 2 showed that the alternative 5'-end is a part of the intron. In addition, the presence of an alternative promoter site, which exists within the intron downstream of the exon 1, became evident. In consequence, the alternative La mRNA is the result of a promoter switching …
Detection, validation, and downstream analysis of allelic variation in gene expression.
2009
AbstractCommon sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control—or cis modulation—rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alter…
Analysis of expression of the gene encoding for the nuclear autoantigen La/SS-B using reporter gene constructs.
1998
In earlier studies mRNA isoforms encoding for the nuclear autoantigen La were identified. In an alternative La mRNA form the exon 1 was replaced with the exon 1'. Moreover, exon 1' La mRNAs were found to start at different 5'-regions. In dependence on the 5'-start the exon 1' La mRNAs encoded for up to three open reading frames upstream of the La frame, which starts in the exon 2. The exon 1' was located in the intron about 70 nts downstream of the exon 1. The exon 1' La mRNA was proposed to be the result of a promoter switch in combination with an alternative splicing mechanism. The commonly used technique to study the expression of a eucaryotic gene is to fuse a reportergene immediately d…
The evolution of splicing: transcriptome complexity and transcript distances implemented in TranD
2021
AbstractAlternative splicing contributes to organismal complexity. Comparing transcripts between and within species is an important first step toward understanding questions about how evolution of transcript structure changes between species and contributes to sub-functionalization. These questions are confounded with issues of data quality and availability. The recent explosion of affordable long read sequencing of mRNA has considerably widened the ability to study transcriptional variation in non-model species. In this work, we develop a computational framework that uses nucleotide resolution distance metrics to compare transcript models for structural phenotypes: total transcript length,…
Generation of GAL4-responsive muscleblind constructs
2002
The muscleblind (mbl) gene encodes protein isoforms Mbl A to Mbl D, which arise by alternative splicing from a common primary transcript. Mbl A, B, and C contain two Zn-finger domains of the type Cys3His, while Mbl D contains only one complete Zn finger. Loss of function mutations in the gene reveal that mbl is involved in both terminal photoreceptor and muscle differentiation in Drosophila. During retina development mbl is essential for rhabdomere differentiation in photoreceptor neuron. Clones homozygous null for mbl completely lack these lightharvesting structures (Begemann et al., 1997). Similarly, the terminal differentiation of the larval body wall muscles is compromised in mbl mutant…