Three novel mutations of the RPGR gene exon ORF15 in three Japanese families with X‐linked retinitis pigmentosa

Abstract

We describe three new mutations in a recently identified exon, ORF15, of the retinitis pigmentosa GTPase regulator gene (RPGR) in three unrelated Japanese families (Families 1-3) with X-linked retinitis pigmentosa (XLRP). The affected males had typical retinitis pigmentosa (RP), whereas the obligate carrier females showed a wide clinical spectrum, ranging from minor symptoms to severe visual disability. Some carrier females in Families 1 and 2 showed typical RP, most carriers manifested high myopia and astigmatism, and their corrected visual acuity was insufficient. They showed an impairment of cone function following the rod dysfunction and accompanied by refractive errors. Microsatellite analysis of Family 1 revealed that the RP in the family was linked to the RP3 locus. Although one patient in the family had no mutation in the previously published exons 1-19 including exon 15a, he had a single-nucleotide insertion in exon ORF15 (g.ORF15 + 753-754 insG). Likewise, patients in Families 2 and 3 had two-base insertion/deletion in the exon, i.e., g.ORF15 + 833-834delGG and g.ORF15 + 861-862insGG, respectively. These insertional/deletional mutations observed in the three families are all different and new, and are predicted to lead to a frameshift, resulting in a truncated protein. These findings may support the previous hypothesis that RPGR-ORF15 is a mutational hot spot.

Age-Dependent Disease Expression Determines Remodeling of the Retinal Mosaic in Carriers ofRPGRExon ORF15 Mutations

“…Female carriers, on the other hand, display a broad spectrum of disease severity. The age of onset and the extent of fundus pigmentary changes, visual field defects and ERG abnormalities vary considerably between and within families 11, 13–15. A characteristic of female XLRP carriers is the patchy nature of the disease expression when assessed by funduscopic examination, Goldmann perimetry11, 16, multifocal ERG17, and histopathology 16, 18–20.…”

Genetics of Refraction and Myopia

“…Ocular or systemic diseases with which high myopia is always observed include: (1) retinitis pigmentosa caused by mutations in RP2 (OMIM 300757) [50][51][52] and RPGR (OMIM 312610) 53 76,77 Interestingly, mutations in NYX have also been reported to cause high myopia without night blindness. 78,79 This opens the possibility that additional mutations in other genes associated with syndromic high myopia may potentially be candidates for nonsyndromic high myopia.…”

A genetic perspective on myopia

“…retinopathy of prematurity following preterm birth and anterior uveitis in JCA. In a number of inherited, especially X-linked retinal disorders, such as retinitis pigmentosa linked to the RP2 and RP3 locus (corresponding to Xp11.23 and Xp21.1, respectively) [16,17] and X-linked congenital stationary night blindness (CSNB1, CSNB 2) [18,19], moderate to high levels of myopia are frequently observed both in affected males and carrier females. In total, there are some 150 genetic syndromes, defined by specific ocular and systemic disorders, that are associated with various levels of myopia.…”