Three novel mutations of theRPGR 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.

Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia

“…Moreover, the co-segregation analysis of this Caucasian family suggests the occurrence of a distinctive X-linked genotype-phenotype correlation between RP and PM, in which a possible complete penetrance of PM trait cannot be ruled out even considering the numerical pedigree’s limitation. In fact, just four female carriers suffered from bilateral myopic chorioretinal degenerations but all of them were heterozygous for ORF15-c.2091_2092insA, indicating that PM could represent the phenotypic expression of RP-related mutant heterozygosities located in various exons of RPGR gene, as previously observed in several pedigrees of both Asian and Caucasian descents202122232425262728. Focusing on the mutational hot spot exon ORF15 of RPGR gene10192930, RP-PM mutations have been hitherto reported exclusively in Asian pedigrees212326, with the exception of the c.2543del variant that has been recently discovered in a family of Caucasian Czech origin28.…”

“…In fact, just four female carriers suffered from bilateral myopic chorioretinal degenerations but all of them were heterozygous for ORF15-c.2091_2092insA, indicating that PM could represent the phenotypic expression of RP-related mutant heterozygosities located in various exons of RPGR gene, as previously observed in several pedigrees of both Asian and Caucasian descents202122232425262728. Focusing on the mutational hot spot exon ORF15 of RPGR gene10192930, RP-PM mutations have been hitherto reported exclusively in Asian pedigrees212326, with the exception of the c.2543del variant that has been recently discovered in a family of Caucasian Czech origin28. In four of these seven RP-PM families with different frame-shift mutations in exon ORF15 of RPGR gene, the variable occurrence of PM among the heterozygous female carriers or between the eyes of the same patients indicates the presence of an incomplete penetrance of this degenerative trait212628.…”

“…Focusing on the mutational hot spot exon ORF15 of RPGR gene10192930, RP-PM mutations have been hitherto reported exclusively in Asian pedigrees212326, with the exception of the c.2543del variant that has been recently discovered in a family of Caucasian Czech origin28. In four of these seven RP-PM families with different frame-shift mutations in exon ORF15 of RPGR gene, the variable occurrence of PM among the heterozygous female carriers or between the eyes of the same patients indicates the presence of an incomplete penetrance of this degenerative trait212628. In fact, an unequivocal PM phenotype, characterized by high myopic refractive error along with myopic fundus appearance, has been detected in both eyes of all RPGR-ORF15 mutant pedigree’s females exclusively in three Asian families2123, and just one of these included more than two heterozygous carriers with PM21 resembling those genealogical features reported for the first time by ours in the present Caucasian family.…”

Screening for mutations in RPGR and RP2 genes in Jordanian families with X-linked retinitis pigmentosa

“…This phenomenon is widely observed in genetic diseases, as the pathogenic locus may be affected by modifying genes and environmental factors. In accordance with this finding, this mutation was reported previously by Bader et al (2003) in XLRP patients and some normal subjects (13%), and has also been documented by others (Roepman et al, 1996;Yokoyama et al, 2001). Alternatively, this mutation may be non-pathogenic but in linkage disequilibrium with another, as yet unknown, pathogenic RPGR sequence variation.…”

“…Openreading frame 15 (ORF15) is the most commonly mutated RPGR exon in XLRP, accounting for 60 to 80% of cases (Vervoort et al, 2000;Pierrottet et al, 2014). ORF15 encodes a sequence of 567 amino acids rich in glutamic acid and glycine at the C-terminus of the RPGR protein (Vervoort et al, 2000;Yokoyama et al, 2001). Mutations in ORF15 have also been identified in X-linked cone-rod dystrophy, which belongs to the same group of retinal dystrophies as typical RP (Ebenezer et al, 2005).…”