A splice-supporting intronic mutation in the last bp position of a cryptic exon within intron 6 of the CYBB gene induces its incorporation into the mRNA causing chronic granulomatous disease (CGD)

Gene
Andreas RumpJoachim Roesler

Abstract

Chronic granulomatous disease (CGD) is caused by a defect in both the host's defenses and its regulation of inflammation normally provided by phagocytes and other leukocytes. As in the case described here, it is not uncommon that CGD patients are diagnosed late, only after organ-damaging manifestations have already progressed. In this patient, we found that CGD arose due to a splice-supporting mutation in the last position of a cryptic exon towards the middle of intron 6 of the CYBB (gp91-phox) gene. The mutation led to the insertion of 56 bp into most of the CYBB mRNA of leukocytes causing a frame shift and a premature stop codon. The normal cryptic exon was also found to be mildly active in some tissues other than leukocytes in healthy donors, to be conserved in many primates, and to a lesser degree in other mammals. Some sequence similarity suggests that the cryptic exon may have originated from a mammalian interspersed repetitive (MIR) element. Taken together, we clarify an unusual disease-causing mutation, indicate its evolutionary background and emphasize the importance of a timely diagnosis of CGD.

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Citations

Oct 14, 2009·Human Genetics·Igor Vorechovsky
May 7, 2011·Antioxidants & Redox Signaling·Michael Li-Hsuan HuangDes R Richardson
Jul 21, 2006·Nucleic Acids Research·Emanuele BurattiFrancisco E Baralle
Nov 10, 2013·International Journal of Cell Biology·Maurizio RomanoDiana Baralle
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Feb 29, 2008·American Journal of Human Genetics·Fanny MochelRonald G Haller
Dec 20, 2018·Frontiers in Immunology·Jesse BruijnesteijnRonald E Bontrop
Apr 1, 2020·F1000Research·Giorgia Bucciol, Isabelle Meyts
May 13, 2017·Human Genetics·Rita Vaz-DragoMaria Carmo-Fonseca
May 11, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Dirk Roos, Martin de Boer

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