Primary immunodeficiency caused by an exonized retroposed gene copy inserted in the CYBB gene

Martin de Boer, Karin van Leeuwen, Judy Geissler, Corry M Weemaes, Timo K van den Berg, Taco W Kuijpers, Adilia Warris, Dirk Roos

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)


Retrotransposon-mediated insertion of a long interspersed nuclear element (LINE)-1 or an Alu element into a human gene is a well-known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X-chromosome. In a Dutch male patient with chronic granulomatous disease, a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense poly(A) tail, target site duplication, and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA.

Original languageEnglish
Pages (from-to)486-96
Number of pages11
JournalHuman mutation
Issue number4
Publication statusPublished - Apr 2014


  • Adult
  • DNA Methylation
  • DNA-Binding Proteins/genetics
  • DNA/analysis
  • Exons
  • Female
  • Granulomatous Disease, Chronic/genetics
  • Humans
  • Introns
  • Long Interspersed Nucleotide Elements
  • Male
  • Membrane Glycoproteins/genetics
  • Mosaicism
  • Mutagenesis, Insertional
  • NADPH Oxidase 2
  • NADPH Oxidases/genetics
  • Netherlands
  • Pedigree
  • RNA Splicing
  • Transcription Factors/genetics
  • Young Adult

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