AN EXON-SKIPPING MUTATION IN THE BTK GENE OF A PATIENT WITH X-LINKED AGAMMAGLOBULINEMIA AND ISOLATED GROWTH-HORMONE DEFICIENCY

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency dis ease associated with a block in differentiation from pre-B to B cells. The XLA gene encodes a 659 amino acids cytoplasmic protein tyrosine k inase named btk (Bruton's tyrosine kinase). The few btk gene alteratio ns so far reported in XLA patients are heterogenous and distributed in all domains of the btk protein. They appear to be responsible for a r ange of B cell immunodeficiency disorders of variable severity. Rare f amilies in which XLA is inherited together with isolated growth hormon e deficiency (IGHD) have been reported. Genetic analysis has shown tha t 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 diff erent developmental or biochemical mechanism is unknown. We have analy sed the btk gene of a patient with XLA and IGHD. RT-PCR analysis of bt k 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 tyrosi ne kinase domain. This exon-skipping event results in a frameshift lea ding to a premature stop codon 14 amino acids downstream, and in the l oss of the last 61 residues of the carboxy-terminal end of the protein . Although we studied a sporadic case, the results suggest that an alt eration of the btk gene might cause this unusual phenotype.