Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa

The gene RPGR was previously identified in the RP3 region of Xp21.1 and sho wn to be mutated in 10-20% of patients with the progressive retinal degener ation X-linked retinitis pigmentosa(1,2) (XLRP). The mutations predominantl y affected a domain homologous to RCC1, a guanine nucleotide exchange facto r for the small GTPase Ran, although they were present in fewer than the 70 -75% of XLRP patients predicted from linkage studies(3-6) Mutations in the RP2 locus at Xp11.3 were found in a further 10-20% of XLRP patients, as pre dicted from linkage studies(6-8). Because the mutations in the remainder of the XLRP patients may reside in undiscovered exons of RPGR, we sequenced a 172-kb region containing the entire gene. Analysis of the sequence disclos ed a new 3' terminal exon that was mutated in 60% of XLRP patients examined . This exon encodes 567 amino acids, with a repetitive domain rich in gluta mic acid residues. The sequence is conserved in the mouse, bovine and Fugu rubripes genes. it is preferentially expressed in mouse and bovine retina, further supporting its importance for retinal function. Our results suggest that mutations in RPGR are the only cause of RP3 type XLRP and account for the disease in over 70% of XLRP patients and an estimated 11% of all retin itis pigmentosa patients.