X-Linked Cone-Rod Dystrophy (Locus COD1): Identification of Mutations in RPGR Exon ORF15

Abstract

X-linked cone-rod dystrophy (COD1) is a retinal disease that primarily affects the cone photoreceptors; the disease was originally mapped to a limited region of Xp11.4. We evaluated the three families from our original study with new markers and clinically reassessed all key recombinants; we determined that the critical intervals in families 2 and 3 overlapped the RP3 locus and that a status change (from affected to probably unaffected) of a key recombinant individual in family 1 also reassigned the disease locus to include RP3 as well. Mutation analysis of the entire RPGR coding region identified two different 2-nucleotide (nt) deletions in ORF15, in family 2 (delAG) and in families 1 and 3 (delGG), both of which result in a frameshift leading to altered amino acid structure and early termination. In addition, an independent individual with X-linked cone-rod dystrophy demonstrated a 1-nt insertion (insA) in ORF15. The presence of three distinct mutations associated with the same disease phenotype provides strong evidence that mutations in RPGR exon ORF15 are responsible for COD1. Genetic heterogeneity was observed in three other families, including the identification of an in-frame 12-nt deletion polymorphism in ORF15 that did not segregate with the disease in one of these families.

Histopathologic study of X-linked cone-rod dystrophy (CORDX1) caused by a mutation in the RPGR exon ORF15

“…2,3 One of our XL CRD families demonstrated 1-nucleotide insertion mutation in exon ORF15 (1564_1565insA; seems to be the most 3= end point mutation published to date). 1 We evaluated the retinal histopathology of an affected 69-yearold family member who had been diagnosed in his 40s based on the following findings in both eyes: decreased VA (20/25), macular depigmentation and granular fine pigment deposits with absent foveal reflex, relative constriction of central VF with full peripheral fields, color vision abnormalities, slightly above normal dark adaptation thresholds, and reduction of cone and rod ERG responses (cone Ͼ rod). His younger brother was diagnosed with "heredomacular degeneration" at age 10.…”

A presumed missense mutation of RPGR causes abnormal RNA splicing with exon skipping

“…1 RPGR exon ORF15 mutations also cause CORDX1 (formerly COD1) type X-linked cone-rod dystrophy (CRD) and atrophic macular degeneration. 2,3 During our RPGR mutation screening of male patients with X-linked or isolated forms of RP or CRD, we identified a novel mutation (213GϾA) that was predicted to cause a nonconservative amino acid change (G52R) in RPGR protein in a patient with isolated RP.…”

“…Gel-purified PCR products were directly sequenced as described. 2 Sequencing of aberrant transcript revealed skipping of exon 2 (126 nt) that would be predicted to generate an RPGR protein with an in-frame deletion of 42 amino acids, affecting the initial part of the critical RCC1-like domain.…”

Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations

“…T he X-linked gene RPGR (retinitis pigmentosa GTPase regulator) is mutated in patients with retinitis pigmentosa type 3 (RP3) (1,2), cone or cone-rod dystrophy (COD1) (3,4), atrophic macular degeneration (5), and RP in combination with impaired hearing and sinorespiratory infections (6). All RP3-associated missense mutations in RPGR have been identified in the N-terminal RCC1-homologous domain, and they disrupt the interaction with the C-terminal domain of RPGR-interacting protein 1 (RPGRIP1) (7,8).…”