An exon-skipping mutation in thebtk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency

AbstractX-linked agammaglobulinemia (XLA) is an inherited immunodeficiency disease associated with a block in differentiation from pre-B to B cells. The XLA gene encodes a 659 amino acids cytoplasmic protein tyrosine kinase namedbtk (Bruton's tyrosine kinase). The fewbtk gene alterations so far reported in XLA patients are heterogenous and distributed in all domains of thebtk protein. They appear to be responsible for a range of B cell immunodeficiency disorders of variable severity. Rare families in which XLA is inherited together with isolated growth hormone deficiency (IGHD) have been reported. Genetic analysis has shown that this disease association maps to the same region of the X chromosome as XLA, but whether the two phenotypes are caused by a common or different developmental or biochemical mechanism is unknown. We have analysed thebtk gene of a patient with XLA and IGHD. RT-PCR analysis ofbtk transcripts, sequencing data obtained from cDNA and genomic DNA and in vitro splicing assays showed that an intronic point mutation (1882 + 5G→A) is responsible for skipping of an exon located in the tyrosine kinase domain. This exon-skipping event results in a frameshift leading to a premature stop codon 14 amino acids downstream, and in the loss of the last 61 residues of the car☐y-terminal end of the protein. Although we studied a sporadic case, the results suggest that an alteration of thebtk gene might cause this unusual phenotype