title: Two independent retrotransposon insertions at the same site within the coding region of BTK.
abstract: Insertion of endogenous retrotransposon sequences accounts for approximately 0.2% of disease causing mutations. These insertions are mediated by the reverse transcriptase and endonuclease activity of long interspersed nucleotide (LINE-1) elements. The factors that control the target site selection in insertional mutagenesis are not well understood. In our analysis of 199 unrelated families with proven mutations in BTK, the gene responsible for X-linked agammaglobulinemia, we identified two families with retrotransposon insertions at exactly the same nucleotide within the coding region of BTK. Both insertions, an SVA element and an AluY sequence, occurred 12 bp before the end of exon 9. Both had the typical hallmarks of a retrotransposon insertion including target site duplication and a long poly A tail. The insertion site is flanked by AluSx sequences 1 kb upstream and 1 kb downstream and an unusual 60 bp sequence consisting of only As and Ts is located in intron 9, 60 bp downstream of the insertion. The occurrence of two retrotransposon sequences at exactly the same site suggests that this site is vulnerable to insertional mutagenesis. A better understanding of the factors that make this site vulnerable will shed light on the mechanisms of LINE-1 mediated insertional mutagenesis.
authors.affiliation: Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee 38105, USA. maryellen.conley@stjude.org
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Conley
authors.forename: Julie D
authors.initials: JD
authors.lastname: Partain
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Norland
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: Haig H
authors.initials: HH
authors.lastname: Kazazian
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics* / Q000628:therapy; D001483:Base Sequence; D041321:Chromosomes, Human, X / Q000235:genetics*; D004252:DNA Mutational Analysis; D004198:Disease Susceptibility; D004827:Epilepsy / Q000235:genetics; D005091:Exons / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007223:Infant; D007239:Infections / Q000209:etiology; D007438:Introns / Q000235:genetics; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D018807:Polymorphism, Single-Stranded Conformational; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012008:Recurrence; D018626:Retroelements / Q000235:genetics*
chemical_list: D016756:Immunoglobulins, Intravenous; D018626:Retroelements; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human