Twin carriers of X-linked agammaglobulinemia (XLA) due to germline mutation in the Btk gene

We report on an X-linked agammaglobulinemia (XLA) family in which mothers o f two affected cousins were monozygotic twins. We analyzed the Btk gene of several members in three generations of the family by SSCP analysis, DNA se quencing, and RFLP analysis following polymerase chain reaction-amplificati on of the individual exons. We identified a missense point mutation, G1817C (R562P), in exon 17 of the Btk gene in the affected cousins. The same muta tion was also present in both mothers (twin sisters) of the cousins identif ying them as carriers, However, the mutation was absent in all other relati ves including the grandmother of the cousins (mother of the twin sisters). This strongly suggests that the mutation in the Btk gene had originated in one of the germ lines or in the zygote, This may be the first demonstration of a germ line (or zygotic) mutation in XLA, (C) 2000 Wiley-Liss, Inc.