Role of 5′‐ and 3′‐untranslated regions of mRNAs in human diseases

Chatterjee, Sangeeta; Pal, Jayanta K.

doi:10.1042/bc20080104

Cited by 375 publications

(292 citation statements)

References 53 publications

(58 reference statements)

Supporting

Mentioning

275

Contrasting

Unclassified

Order By: Relevance

“…This is a sequence motif recognised by RNA-binding factors and is essential for transcriptional termination and efficient polyadenylation of mRNAs and release of the polyadenylated mRNA for export from the nucleus. 26 Mutations affecting a polyadenylation signal and the secondary structure of the 3¢-UTR of mRNA have been shown to cause translation de-regulation 27 and have been reported in other diseases. [28][29][30][31] It is therefore predicted that deletion of this signal in TCOF1 would lead to reduced accumulation of treacle, consistent with a mechanism of haploinsufficiency in TCS.…”

Section: Discussionmentioning

confidence: 99%

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

et al. 2012

View full text Add to dashboard Cite

Treacher-Collins-Franceschetti syndrome (TCS) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia, micrognathia, downslanting palpebral fissures, eyelid colobomata, and ear deformities that often lead to conductive deafness. A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene. In all, 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion. A further case had a novel in-frame deletion in the alternatively spliced exon 6A of uncertain pathogenicity. The majority of the pathogenic sequence changes were found to predict premature protein termination, however, four novel missense changes in the LIS1 homology motif at the 5¢ end of the gene were identified. The partial gene deletions of different sizes represent B5.2% of all the pathogenic TCOF1 mutations identified, indicating that gene rearrangements account for a significant proportion of TCS cases. This is the first report of gene rearrangements resulting in TCS. These findings expand the TCOF1 mutation spectrum indicating that dosage analysis should be performed together with sequence analysis, a strategy that is predicted to have a sensitivity of 71% for patients in whom TCS is strongly suspected.

show abstract

Section: Discussionmentioning

confidence: 99%

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

et al. 2012

View full text Add to dashboard Cite

show abstract

“…We decided to test hypotheses reflecting two prevalent mechanisms of translational regulation by 5′-UTR elements; one would decrease and the other would increase translational efficiency. In the first hypothesis, Alu exons may introduce or elongate uORFs before the primary start codons, thus repressing the translation of the primary ORFs (37,38). In the second hypothesis, Alu exons could introduce cellular IRES elements to the 5′-UTRs and thus increase translational efficiency (37).…”

Section: Molecular Mechanisms Of Translational Regulation By Alu Exonsmentioning

confidence: 99%

“…Newly created 5′-UTR Alu exons potentially could regulate translational efficiency through a variety of molecular mechanisms, such as upstream ORF (uORF), IRES, secondary structure, and 5′-UTR length (37). We decided to test hypotheses reflecting two prevalent mechanisms of translational regulation by 5′-UTR elements; one would decrease and the other would increase translational efficiency.…”

Section: Molecular Mechanisms Of Translational Regulation By Alu Exonsmentioning

confidence: 99%

Widespread establishment and regulatory impact of Alu exons in human genes

Shen¹,

Lin²,

Cai

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

125

113

View full text Add to dashboard Cite

The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. However, identifying Alu exons that have acquired genuine biological functions remains a major challenge. We investigated the creation and establishment of Alu exons in human genes, using transcriptome profiles of human tissues generated by high-throughput RNA sequencing (RNA-Seq) combined with extensive RT-PCR analysis. More than 25% of Alu exons analyzed by RNASeq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. Genes encoding zinc finger transcription factors have significantly higher levels of Alu exonization. Importantly, Alu exons with high splicing activities are strongly enriched in the 5′-UTR, and two-thirds (10/15) of 5′-UTR Alu exons tested by luciferase reporter assays significantly alter mRNA translational efficiency. Mutational analysis reveals the specific molecular mechanisms by which newly created 5′-UTR Alu exons modulate translational efficiency, such as the creation or elongation of upstream ORFs that repress the translation of the primary ORFs. This study presents genomic evidence that a major functional consequence of Alu exonization is the lineagespecific evolution of translational regulation. Moreover, the preferential creation and establishment of Alu exons in zinc finger genes suggest that Alu exonization may have globally affected the evolution of primate and human transcriptomes by regulating the protein production of master transcriptional regulators in specific lineages. transcriptome evolution | transposable element | alternative splicing | deep sequencing | uORF

show abstract

“…30 So far, many diseases are associated to improper functioning, caused for example by point mutations, of any of the 5'UTR cis-regulatory elements mentioned above. 31 Reports differ on the PTCH1b 5'UTR length: in the NCBI GenBank it is annotated as 188-nucleotide long (RefSeq ID NM_000264.3), while in Ensembl it includes additional 112 nucleotides upstream, for a total length of 300 nucleotides (Transcript ID ENST00000331920.6). Even longer PTCH1b 372 nucleotides long 5'UTR was reported.…”

Section: Introductionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

View full text Add to dashboard Cite

Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

show abstract

Role of 5′‐ and 3′‐untranslated regions of mRNAs in human diseases

Cited by 375 publications

References 53 publications

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

Widespread establishment and regulatory impact of Alu exons in human genes

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

Contact Info

Product

Resources

About