title: 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).
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.
authors.affiliation: Institute of Human and Clinical Genetics, University Clinic Carl Gustav Carus, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.forename: Angela
authors.initials: A
authors.lastname: Rösen-Wolff
authors.forename: Manfred
authors.initials: M
authors.lastname: Gahr
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seidenberg
authors.forename: Christian
authors.initials: C
authors.lastname: Roos
authors.forename: Lutz
authors.initials: L
authors.lastname: Walter
authors.forename: Viola
authors.initials: V
authors.lastname: Günther
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D018076:DNA, Complementary; D005091:Exons; D020869:Gene Expression Profiling; D006105:Granulomatous Disease, Chronic / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases