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Related Concept Videos

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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised  of nucleotides and proteins are comprised of amino acids, a mediator is required to convert the information encoded in DNA into proteins. This mediator is the messenger RNA (mRNA). mRNA copies the blueprint from DNA by a process called transcription. In eukaryotes, transcription occurs in the nucleus by complementary base-pairing with the DNA template. The mRNA is then...
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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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Translation01:31

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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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Ribosome profiling or ribo-sequencing is a deep sequencing technique that produces a snapshot of active translation in a cell. It selectively sequences the mRNAs protected by ribosomes to get an insight into a cell’s translation landscape at any given point in time.
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Updated: Oct 17, 2025

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Genetic variants in progranulin upstream open reading frames increase downstream protein expression.

Alexandros Frydas1, Rita Cacace1, Julie van der Zee1

  • 1VIB Center for Molecular Neurology, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

Neurobiology of Aging
|October 8, 2021
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Summary

Genetic variants in granulin gene (GRN) upstream open reading frames (uORFs) can alter progranulin protein (PGRN) levels. This discovery offers new insights into frontotemporal lobar degeneration (FTLD) pathogenesis.

Keywords:
FTDFrontotemporal lobar degenerationGRN genePGRN proteinRare genetic variantsUpstream open reading frame

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Area of Science:

  • Neurogenetics
  • Molecular Biology
  • Human Genetics

Background:

  • Premature termination codon (PTC) mutations in the granulin gene (GRN) cause progranulin protein (PGRN) loss-of-function (LOF), leading to frontotemporal lobar degeneration (FTLD) via haploinsufficiency.
  • GRN gene expression is regulated by its 5' untranslated region (UTR), which contains upstream open reading frames (uORFs) that typically repress translation.
  • Disruption of these uORFs can increase PGRN protein levels.

Purpose of the Study:

  • To investigate the role of GRN 5' UTR uORFs in regulating PGRN expression.
  • To identify genetic variants within GRN uORFs in patients with frontotemporal dementia (FTD).
  • To determine the functional impact of identified variants on PGRN protein levels.

Main Methods:

  • Targeted sequencing of GRN 5' UTR uORF regions in a Flanders-Belgian FTD patient cohort.
  • Analysis of genetic variants and their potential impact on uORF function.
  • Quantification of PGRN protein expression levels in relation to identified variants.

Main Results:

  • Two genetic variants were identified in the uORF regions of both the main and alternative 5' UTRs of GRN.
  • Both identified variants were shown to increase downstream PGRN protein levels.
  • A specific variant, rs76783532 in the main 5' UTR, resulted in a significant 1.5-fold increase in PGRN protein expression.

Conclusions:

  • Functional uORFs in the alternative 5' UTR of GRN are significant regulators of PGRN expression.
  • Genetic variations within GRN uORFs can alter their regulatory function.
  • These findings provide novel insights into the molecular mechanisms underlying FTLD and highlight GRN uORFs as potential therapeutic targets.