title: Discordant phenotype in siblings with X-linked agammaglobulinemia.
abstract: X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused by a defect in a B-cell-specific signaling molecule, Btk. There has been little concordance of phenotype with genotype in this disorder, and defects in Btk cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. The current study is the first description of two male siblings with identical T134 --> C mutations in the translation initiation ATG of Btk who have different clinical phenotypes. The proband lacks immunoglobulins and B cells and has recurrent infections, while the elder, affected brother has normal levels of IgG and IgM and very few infections. Both have undetectable levels of Btk kinase activity in circulating mononuclear cells. Complete sequencing of Btk gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. This description provides unequivocal evidence that the phenotype of XLA is influenced by factors additional to the Btk gene.
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bykowsky
authors.forename: R N
authors.initials: RN
authors.lastname: Haire
authors.forename: Y
authors.initials: Y
authors.lastname: Ohta
authors.forename: H
authors.initials: H
authors.lastname: Tang
authors.forename: S S
authors.initials: SS
authors.lastname: Sung
authors.forename: E S
authors.initials: ES
authors.lastname: Veksler
authors.forename: J M
authors.initials: JM
authors.lastname: Greene
authors.forename: S M
authors.initials: SM
authors.lastname: Fu
authors.forename: G W
authors.initials: GW
authors.lastname: Litman
authors.forename: K E
authors.initials: KE
authors.lastname: Sullivan
mesh_terms: D000293:Adolescent; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000235:genetics*; D001402:B-Lymphocytes / Q000201:enzymology; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D016131:Lymphocyte Subsets; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology; D009679:Nuclear Family; D010641:Phenotype; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology; D014960:X Chromosome
chemical_list: D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human