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*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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)486-496
Number of pages11
JournalHuman Mutation
Volume35
Issue number4
Early online date24 Feb 2014
DOIs
Publication statusPublished - Apr 2014

Fingerprint

Exons
Mothers
Alu Elements
Genes
Chronic Granulomatous Disease
X-Linked Genes
Retroelements
Messenger RNA
Chromosomes, Human, Pair 3
Mosaicism
Nonsense Codon
Insertional Mutagenesis
Endonucleases
DNA
Fetal Development
Introns
Consensus
Parents
Alleles
Mutation

Keywords

  • Chronic granulomatous disease
  • CYBB
  • Gene copy retroposition
  • TMF1
  • X-chromosome inactivation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)

Cite this

de Boer, M., van Leeuwen, K., Geissler, J., Weemaes, C. M., van den Berg, T. K., Kuijpers, T. W., ... Roos, D. (2014). Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene. Human Mutation, 35(4), 486-496. https://doi.org/10.1002/humu.22519

Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene. / de Boer, Martin; van Leeuwen, Karin; Geissler, Judy; Weemaes, Corry M.; van den Berg, Timo K.; Kuijpers, Taco W.; Warris, Adilia; Roos, Dirk.

In: Human Mutation, Vol. 35, No. 4, 04.2014, p. 486-496.

Research output: Contribution to journalArticle

de Boer, M, van Leeuwen, K, Geissler, J, Weemaes, CM, van den Berg, TK, Kuijpers, TW, Warris, A & Roos, D 2014, 'Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene', Human Mutation, vol. 35, no. 4, pp. 486-496. https://doi.org/10.1002/humu.22519
de Boer M, van Leeuwen K, Geissler J, Weemaes CM, van den Berg TK, Kuijpers TW et al. Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene. Human Mutation. 2014 Apr;35(4):486-496. https://doi.org/10.1002/humu.22519
de Boer, Martin ; van Leeuwen, Karin ; Geissler, Judy ; Weemaes, Corry M. ; van den Berg, Timo K. ; Kuijpers, Taco W. ; Warris, Adilia ; Roos, Dirk. / Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene. In: Human Mutation. 2014 ; Vol. 35, No. 4. pp. 486-496.
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