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Related Concept Videos

RNA Splicing01:32

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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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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
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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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Translation01:31

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Lesson: Translation
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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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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Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
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POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy.

Hitoshi Kashiki1, Heng Li1, Sachiko Miyamoto1

  • 1Department of Pediatrics (H.K.), Minamata City General Hospital & Medical Center, Kumamoto; Department of Mental Retardation and Birth Defect Research (H.L., K.I.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo; Department of Biochemistry (S.M., H.S.), Hamamatsu University School of Medicine, Shizuoka; Department of Pediatrics (H.U.), Kumamoto Takumadai Rehabilitation Hospital; Kanagawa Children's Medical Center (Y.T., Y.E.), Clinical Research Institute, Yokohama, Kanagawa; Department of Pediatrics (C.I., H.K., T.O., T.S., H.I.), National Hospital Organization Kumamoto Saishun Medical Center, Koshi; Clinical Research Institute, Kanagawa Children's Medical Center, (Y.E.), Yokohama, Kanagawa; Department of Pediatric Neurology (J.T.), Tokyo Women's Medical University Yachiyo Medical Center, Chiba; and Division of Medical Genetics (K.K.), Kanagawa Children's Medical Center, Yokohama, Japan.

Neurology. Genetics
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Summary

Novel POLR1C variants cause RNA polymerase III leukodystrophy through splicing dysregulation. This study reveals a broad clinical spectrum and identifies abnormal splicing as a key pathomechanism.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • RNA polymerase III (Pol III)-related leukodystrophy is a rare genetic disorder.
  • Biallelic variants in POLR1C are implicated in this condition.
  • The precise molecular pathogenesis remains incompletely understood.

Purpose of the Study:

  • To elucidate the cellular mechanisms underlying POLR1C-related leukodystrophy.
  • To investigate the impact of POLR1C variants on downstream gene expression.
  • To characterize the splicing defects caused by POLR1C mutations.

Main Methods:

  • Exome sequencing was performed to identify genetic variants.
  • Cellular expression studies were utilized to assess protein function.
  • Long-read sequencing analyzed transcriptomic alterations, including splicing patterns.

Main Results:

  • Novel biallelic POLR1C variants (c.167T>A, p.M56K and c.595A>T, p.I199F) were identified as causal.
  • These variants led to altered protein localization, reduced expression, and significant intron inclusion in POLR1C transcripts.
  • Aberrant splicing was observed in both mutant and wild-type alleles in heterozygous carriers, indicating a downstream effect.

Conclusions:

  • The clinical presentation in this family highlights the broad spectrum of Pol III-related leukodystrophy.
  • Dysregulation of splicing is proposed as a critical downstream pathomechanism for POLR1C variants.
  • These findings advance our understanding of the molecular basis of leukodystrophies.