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Processed pseudogene insertion in GLB1 causes Morquio B disease by altering intronic splicing regulatory landscape

Igor Bychkov1, Antonina Kuznetsova2, Galina Baydakova2

  • 1Research Centre for Medical Genetics, Moscow, Russia. bychkov@med-gen.ru.

NPJ Genomic Medicine
|July 26, 2022
PubMed

Insights

This study details a unique case of Morquio B disease caused by a retrotransposon insertion. Researchers identified a mechanism altering gene splicing and demonstrated a potential personalized genetic therapy approach.

Area of Science:

  • Genetics
  • Molecular Biology
  • Medical Science

Background:

  • Morquio B disease (MBD) is a rare, mild form of lysosomal storage disease linked to the GLB1 gene.
  • Genetic variations in GLB1 can cause MBD, but the specific mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the molecular genetic cause of a unique case of "pure" Morquio B disease.
  • To elucidate the pathogenic mechanism involving a mobile genetic element insertion.
  • To explore potential therapeutic strategies based on correcting aberrant gene splicing.

Main Methods:

  • Whole-genome sequencing (WGS) to identify genetic variants.
  • mRNA analysis to study gene expression.
  • Functional analysis using minigenes and splice-modulating oligonucleotides (ASMOs).
  • Modified U7 small nuclear RNA (modU7snRNA) for targeted splicing correction.

Main Results:

  • Identified insertion of a processed pseudogene (NPM1) into intron 5 of the GLB1 gene.
  • Demonstrated that the pseudogene insertion alters GLB1 splicing by activating a cryptic exon.
  • Showed that ASMOs delivered via modU7snRNA can restore normal GLB1 splicing in vitro.
  • This represents the second reported case of processed pseudogene insertion causing monogenic disorders.

Conclusions:

  • The study highlights the role of retrotransposon insertions in causing rare genetic disorders like MBD.
  • Aberrant splicing due to pseudogene insertion is a key pathogenic mechanism.
  • Personalized genetic therapy targeting splicing defects shows promise for MBD treatment.
  • WGS is crucial for identifying complex genetic variants underlying rare diseases.

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