An atypical phenotype of macular and peripapillary retinal atrophy caused by a mutation in the RP2 gene.(Extended Report)

Br J Ophthalmol 2004;88:528-532. doi: 10.1136/bjo.2003.027979

Aims: To determine the molecular basis and describe the phenotype of an atypical retinal dystrophy in a family presenting with bilateral, progressive central visual loss.

Methods: Family members were examined. Investigations included Goldman perimetry, electrophysiology, and autofluorescence imaging. Candidate gene screening was performed using SSCP and sequence analysis. The proband's lymphoblastoid cells were examined for protein expression.

Results: Fundal examination of the proband, his mother, and brother revealed peripapillary and macular atrophy. Autosomal dominant retinal dystrophy was suspected, but less severe disease in the mother led to screening for mutations in X linked genes. A 4 bp microdeletion in exon 3 of the RP2 gene, segregating with disease, was identified. No RP2 protein expression was detected.

Conclusion: The distinct phenotype in this family, caused by this frameshifting mutation in RP2, broadens the phenotypic spectrum of X linked retinitis pigmentosa. The absence of RP2 protein suggests that loss of protein function and not novel gain of function could account for the atypical phenotype. A definitive diagnosis of X linked retinitis pigmentosa permits appropriate genetic counselling with important implications for other family members. Clinicians should have a low threshold for screening RP2 in families with retinal dystrophy, including posterior retinal disease, not immediately suggestive of X linked inheritance.

**********

Retinitis pigmentosa (RP) defines a clinically and genetically diverse group of retinal dystrophies characterised by progressive photoreceptor cell degeneration. X linked retinitis pigmentosa (XLRP) affects about 10-20% of families with RP. (1-3) It is a severe form of RP in terms of age of onset and progression, typically presenting with symptoms of night blindness and loss of dark adaptation within the first decade of life and reduction of visual fields in the second decade. (1) Disease may progress to complete blindness by the third or fourth decade. Premature cell death occurs initially in the mid-periphery of the retina and primarily affects rod photoreceptors. Clinically this is seen as bone spicules in the periphery caused by pigment epithelial atrophy and pigment migration into the retina. Other signs in the late stages of this degenerative disease include optic atrophy and attenuated blood vessels. (1 2)

Five loci have been mapped for XLRP, of which RP3 and RP2 account for the majority of disease. (4-7) Positional cloning resulted in the identification of the highly complex RPGR (RP guanosine triphosphatase (GTPase) regulator) gene in the RP3 region (8-10) and the RP2 gene in the RP2 region. (11) Many different mutations have been described in RPGR and RP2 as a cause of XLRP. Mutations in RPGR, including the more recently identified ORF15, are the most common and account for approximately 70-90% of XLRP cases. (8-10 12-18) RP2, the second most frequent cause of XLRP, accounts for approximately 6-20% of cases in the populations studied. (11-13 19-22) The RP2 gene has 5 exons and encodes a 350 amino acid polypeptide (RP2) which is ubiquitously expressed. (23 24) RP2 shows homology to cofactor C, which functions in the assembly of native tubulin heterodimers with other cofactors (A-E). (25 26) Missense, nonsense, frameshift, insertion, and deletion mutations have been identified in the RP2 gene, many of which occur at residues conserved with cofactor C, …