Novel Mutations of RPGR in Chinese Retinitis Pigmentosa Patients and the Genotype-Phenotype Correlation

Abstract

X-linked Retinitis Pigmentosa (XLRP) accounts for 10–20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70–75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.

Visual Function in Carriers of X-Linked Retinitis Pigmentosa

“…This is in agreement with one study that found worse function in ORF15 families 10 , but is in contrast to other studies 7,22,23,29 in males with RPGR mutations which showed an effect in the opposite direction. The reason for this is not known.…”

“…27 In fact, the observed loss of visual acuity and 30 Hz ERG (cone) amplitude compared to the relatively preserved visual field area and 0.5 Hz ERG (cone-plus-rod) amplitude suggest that the XLRP carrier state is a cone-predominant phenotype; a similar pattern has been previously reported in XLRP males, especially in males with mutations near the 3’ end of RPGR ORF15. 22,29 …”

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.…”

“…Starting from the first analytical report on the refractive errors of RP patients, mild-to-high myopia has been described as a very frequent feature in the majority of affected family members with X-linked disease42. Moreover, in families without male-to-male RP transmission, myopia, associated with highly variable degenerative chorioretinal changes, is present in many women20212223242526272831383940. Even if the skewed X-chromosome inactivation should be the key factor implicated in the wide inter-individual and inter-ocular diversity of the expression of these myopic traits1124, other unknown genetic modifiers could contribute to the phenotypic heterogeneity of PM in heterozygous female carriers of X-linked RP mutations.…”

RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options

“…However, there remains significant intrafamilial and interfamilial variability with examples of RP and CORD within the same families despite the same underlying sequence variant in RPGR ,61 65 66 suggesting that genetic and/or environmental modifiers are also influencing phenotype.…”