title: Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations.
abstract: X-linked agammaglobulinemia is caused by mutations in the human BTK gene, leading to recurrent pyogenic infections. We describe four novel and three known BTK-mutations in seven patients from seven (six Thai and one Burmese) families. All but one were sporadic cases. Patients 1 and 2 had recurrent mutations in exon 10 (R288W) and exon 17 (R562W), respectively. Patient 3, a previously healthy individual who presented with pseudomonas sepsis with ecthyma gangrenosum had a known mutation in exon 17 (1749delT), leading to frameshift effect (F583fsX586). Patient 4 manifested with sepsis and concurrent acute appendicitis and pneumonia. He had a mutation, IVS8 + 1G > A, which led to an insertion of intron 8 into the transcripts. In Patient 5, a novel change in exon 7, c.588G > C, initially presumed Q196H, was found to cause a leaky splicing mutation, resulting in three distinct transcripts containing 17, 108, and 190 bp of the 5'-terminal of intron 7, which led to truncated peptides consisting of 203 and 211 amino acid residues (or Q196fsX204 and Q196fsX212, respectively). Patient 6 had a mutation in exon 14 (W421X), while patient 7 had a newly defined large deletion of exons 6-9. All of the mothers tested were mutation carriers. Transcript analysis in three mothers who were heterozygous for frameshift mutations revealed a minimal amount of aberrant transcripts, while their affected children had full expression of the mutant alleles, suggesting rapid degradation due to nonsense-mediated mRNA decay in the mothers. This is the first report of mutations of BTK from Thailand.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand. radwc@mahidol.ac.th.
authors.forename: Duangrurdee
authors.initials: D
authors.lastname: Wattanasirichaigoon
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand.
authors.forename: Suwat
authors.initials: S
authors.lastname: Benjaponpitak
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand.
authors.forename: Chonnamet
authors.initials: C
authors.lastname: Techasaensiri
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand.
authors.forename: Wasu
authors.initials: W
authors.lastname: Kamchaisatian
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Pakit
authors.initials: P
authors.lastname: Vichyanond
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Sucheela
authors.initials: S
authors.lastname: Janwityanujit
authors.affiliation: Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Lulin
authors.initials: L
authors.lastname: Choubtum
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama VI Road, Bangkok, 10400, Thailand.
authors.forename: Sayomporn
authors.initials: S
authors.lastname: Sirinavin
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics*; D000483:Alleles; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D005091:Exons; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human