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1.
Int J Mol Sci ; 19(5)2018 May 08.
Article in English | MEDLINE | ID: mdl-29738455

ABSTRACT

The aim of this research was the identification of novel pharmacogenomic biomarkers for better understanding the complex gene regulation mechanisms underpinning glucocorticoid (GC) action in paediatric inflammatory bowel disease (IBD). This goal was achieved by evaluating high-throughput microRNA (miRNA) profiles during GC treatment, integrated with the assessment of expression changes in GC receptor (GR) heterocomplex genes. Furthermore, we tested the hypothesis that differentially expressed miRNAs could be directly regulated by GCs through investigating the presence of GC responsive elements (GREs) in their gene promoters. Ten IBD paediatric patients responding to GCs were enrolled. Peripheral blood was obtained at diagnosis (T0) and after four weeks of steroid treatment (T4). MicroRNA profiles were analyzed using next generation sequencing, and selected significantly differentially expressed miRNAs were validated by quantitative reverse transcription-polymerase chain reaction. In detail, 18 miRNAs were differentially expressed from T0 to T4, 16 of which were upregulated and 2 of which were downregulated. Out of these, three miRNAs (miR-144, miR-142, and miR-96) could putatively recognize the 3’UTR of the GR gene and three miRNAs (miR-363, miR-96, miR-142) contained GREs sequences, thereby potentially enabling direct regulation by the GR. In conclusion, we identified miRNAs differently expressed during GC treatment and miRNAs which could be directly regulated by GCs in blood cells of young IBD patients. These results could represent a first step towards their translation as pharmacogenomic biomarkers.


Subject(s)
Biomarkers , Glucocorticoids/adverse effects , Inflammatory Bowel Diseases/drug therapy , MicroRNAs/genetics , Adolescent , Child , Female , Gene Expression Regulation/drug effects , Glucocorticoids/administration & dosage , High-Throughput Nucleotide Sequencing , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathology , Male , Receptors, Glucocorticoid/genetics , Transcriptome/drug effects
2.
BMC Plant Biol ; 14: 99, 2014 Apr 17.
Article in English | MEDLINE | ID: mdl-24739459

ABSTRACT

BACKGROUND: Alternative splicing (AS) significantly enhances transcriptome complexity. It is differentially regulated in a wide variety of cell types and plays a role in several cellular processes. Here we describe a detailed survey of alternative splicing in grape based on 124 SOLiD RNAseq analyses from different tissues, stress conditions and genotypes. RESULTS: We used the RNAseq data to update the existing grape gene prediction with 2,258 new coding genes and 3,336 putative long non-coding RNAs. Several gene structures have been improved and alternative splicing was described for about 30% of the genes. A link between AS and miRNAs was shown in 139 genes where we found that AS affects the miRNA target site. A quantitative analysis of the isoforms indicated that most of the spliced genes have one major isoform and tend to simultaneously co-express a low number of isoforms, typically two, with intron retention being the most frequent alternative splicing event. CONCLUSIONS: As described in Arabidopsis, also grape displays a marked AS tissue-specificity, while stress conditions produce splicing changes to a minor extent. Surprisingly, some distinctive splicing features were also observed between genotypes. This was further supported by the observation that the panel of Serine/Arginine-rich splicing factors show a few, but very marked differences between genotypes. The finding that a part the splicing machinery can change in closely related organisms can lead to some interesting hypotheses for evolutionary adaptation, that could be particularly relevant in the response to sudden and strong selective pressures.


Subject(s)
Alternative Splicing/genetics , Organ Specificity/genetics , Stress, Physiological/genetics , Vitis/genetics , Adaptation, Physiological/genetics , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Databases, Genetic , Databases, Nucleic Acid , Evolution, Molecular , Gene Expression Regulation, Plant , Genes, Plant , Genotype , MicroRNAs/genetics , MicroRNAs/metabolism , Principal Component Analysis , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Untranslated/genetics , RNA, Untranslated/metabolism
3.
Epilepsia ; 44(10): 1289-97, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14510822

ABSTRACT

PURPOSE: [corrected] To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE). METHODS: A personal and family history was obtained from each affected and unaffected member, along with a physical and neurologic examination. Routine and sleep EEGs, computed tomography (CT), or magnetic resonance imaging (MRI) were performed in almost all the patients. DNAs from family members were typed with several microsatellite markers localized on either side of LGI1 at 10q24 and screened for LGI1 mutations. RESULTS: The seven families included a total of 34 affected individuals (10 deceased). The age at onset ranged between 8 and 50 years (average, 22 years). Twenty-six patients had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Less frequent ictal symptoms were visual, psychic, or aphasic seizures, the latter occurring in isolation in one family. The attacks were rare and well controlled by antiepileptic drug treatment but recurred after drug discontinuation. Interictal EEGs were usually unrevealing. MRI or CT scans were negative. Analysis of LGI1/Epitempin exons failed to show mutations in three pedigrees. Linkage analysis strongly suggested exclusion of linkage in one of these families. We found two novel missense mutations, a T-->C substitution in exon 6 at position 598, and a T-->A transition in exon 8 at position 1295, the latter being detected in a family with aphasic seizures. CONCLUSIONS: Our data confirm the inclusion of aphasic seizures within the ADLTE clinical spectrum, suggest the existence of locus heterogeneity in ADLTE, and provide new familial cases with LGI1 missense mutations associated with the disease.


Subject(s)
Epilepsy, Temporal Lobe/genetics , Genetic Heterogeneity , Mutation , Proteins/genetics , Adolescent , Adult , Child , Europe , Female , Genes, Dominant , Genetic Linkage , Humans , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Pedigree
4.
Biochem Biophys Res Commun ; 309(2): 391-8, 2003 Sep 19.
Article in English | MEDLINE | ID: mdl-12951062

ABSTRACT

About 10% of cases of hypertrophic cardiomyopathy (HCM) evolve into dilated cardiomyopathy (DCM) with unknown causes. We studied 11 unrelated patients (pts) with HCM who progressed to DCM (group A) and 11 who showed "typical" HCM (group B). Mutational analysis of the beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) genes demonstrated eight mutations affecting MYH7 or MYBPC3 gene, five of which were new mutations. In group A-pts, the first new mutation occurred in the myosin head-rod junction and the second occurred in the light chain-binding site. The third new mutation leads to a MYBPC3 lacking titin and myosin binding sites. In group B, two pts with severe HCM carried two homozygous MYBPC3 mutations and one with moderate hypertrophy was a compound heterozygous for MYBPC3 gene. We identified five unreported mutations, potentially "malignant" defects as for the associated phenotypes, but no specific mutations of HCM/DCM.


Subject(s)
Cardiomyopathy, Dilated/classification , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Hypertrophic, Familial/classification , Cardiomyopathy, Hypertrophic, Familial/genetics , DNA Mutational Analysis/methods , Genetic Predisposition to Disease/genetics , Muscle Proteins/genetics , Adult , Aged , Amino Acid Sequence , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Hypertrophic, Familial/diagnosis , Carrier Proteins/blood , Carrier Proteins/genetics , Carrier Proteins/metabolism , Female , Homozygote , Humans , Male , Middle Aged , Molecular Sequence Data , Muscle Proteins/metabolism , Mutation , Sequence Alignment , Sequence Analysis, Protein , Troponin T/blood , Troponin T/genetics , Troponin T/metabolism , Ventricular Myosins/blood , Ventricular Myosins/genetics , Ventricular Myosins/metabolism
5.
Am J Hum Genet ; 71(5): 1200-6, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12373648

ABSTRACT

Arrhythmogenic right ventricular cardiomyopathy (ARVD/C) is a genetically heterogeneous disease characterized by progressive degeneration of the right ventricular myocardium and increased risk of sudden death. Here, we report on a genome scan in one Italian family in which the disease appeared unlinked to any of the six different ARVD loci reported so far; we identify a mutation (S299R) in exon 7 of desmoplakin (DSP), which modifies a putative phosphorylation site in the N-terminal domain binding plakoglobin. It is interesting that a nonsense DSP mutation was reported elsewhere in the literature, inherited as a recessive trait and causing a biventricular dilative cardiomyopathy associated with palmoplantar keratoderma and woolly hairs. Therefore, different DSP mutations might produce different clinical phenotypes, with different modes of inheritance.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/genetics , Cytoskeletal Proteins/genetics , Adolescent , Aged , Amino Acid Sequence , Cytoskeletal Proteins/metabolism , Desmoplakins , Female , Genes, Dominant , Genetic Markers , Humans , Male , Molecular Sequence Data , Pedigree , Point Mutation , gamma Catenin
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