X-linked forms of retinitis pigmentosa (XLRP) are relatively severe with clinical, genetic, and even allelic heterogeneity. Mutations in the retinitis pigmentosa guanosine triphosphatase regulator (
RPGR) gene account for over 70% of XLRP and are even reported in patients with divergent retinal degenerative diseases, including cone dystrophies and macular degeneration.
1 RPGR and its interacting proteins in the cilium have been associated with photoreceptor dysfunction/death in many syndromic diseases.
2 A recent study identified
RPGR mutations in a considerable proportion of males (29 of 214 examined) with simplex retinal degeneration phenotypes.
3 Mutations in another XLRP gene,
RP2, were detected in three other patients. In this issue,
Churchill et al. 4 provide another twist to the RPGR saga by examining a cohort of 258 families that were initially categorized as autosomal dominant RP (adRP) based on the pedigree analysis. Of these, 95 families did not carry mutations in known adRP genes. These authors screened 56 of the 95 families that did not show male-to-male transmission. Interestingly, 20 families had mutations in
RPGR and two others in
RP2. Not unexpectedly, 12 of the 20
RPGR mutations were found in the ORF15 exon. Thus,
RPGR mutations accounted for one-third of the families after known adRP genes had been excluded, and represented almost 8% of the adRP cohort being investigated by Churchill et al., second only to rhodopsin and equal to
PRPF31 and
PRPH2 (
RDS).
5 These findings have significant clinical implications as RPGR now occupies a prominent causative role in inherited retinopathies, exhibiting divergent clinical phenotypes and genetic spectrum.