title: Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements.
abstract: Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions ( approximately 60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease.
authors.affiliation: Department of Immunology, Erasmus MC, 3015 GE Rotterdam, the Netherlands.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: Corinne
authors.initials: C
authors.lastname: Geertsema
authors.forename: Nicole
authors.initials: N
authors.lastname: Nieuwenhuis
authors.forename: Dick
authors.initials: D
authors.lastname: de Ridder
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Conley
authors.forename: Claudine
authors.initials: C
authors.lastname: Schiff
authors.forename: Ilhan
authors.initials: I
authors.lastname: Tezcan
authors.forename: Ewa
authors.initials: E
authors.lastname: Bernatowska
authors.forename: Nico G
authors.initials: NG
authors.lastname: Hartwig
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Sanders
authors.forename: Jiri
authors.initials: J
authors.lastname: Litzman
authors.forename: Irina
authors.initials: I
authors.lastname: Kondratenko
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001483:Base Sequence; D053960:DNA Breaks; D004251:DNA Transposable Elements / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins; D004720:Endonucleases; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics*; D020071:Interspersed Repetitive Sequences / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D007148:Immunoglobulin mu-Chains; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C426344:DCLRE1C protein, human; D004720:Endonucleases