Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS gene

Abstract

ABSTRACT.Purpose: This study aimed to identify the genetic cause of autosomal dominant pericentral retinal dystrophy (adPRD) in a large Norwegian family with 35 affected members. Methods: The family was characterized by clinical ophthalmological examination along with fundus photography, dark adaptometry and electroretinography. We performed a genome-wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease. Results: The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis. Linkage analysis showed a linkage peak covering the most recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a novel missense mutation, c.1205a>c, resulting in an amino acid substitution p.Q402P, was detected in all affected members. The mutation showed complete co-segregation with the disease in this family, with a LOD score of 7.3. It is located in a highly conserved region and alignment with the appropriate DNA sequence from other species shows complete conservation of this amino acid. The mutation was not detected in 207 healthy, unrelated controls of Norwegian origin. Conclusions: We present a novel mutation in the TOPORS gene co-segregating with a distinct phenotype of adPRD in a large Norwegian family.

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

“…11,12,17 Common to the three studies are data for visual acuities and ERGs. One study was mainly of simplex RP patients with a pericentral distribution of disease.…”

“…Five patients from ad pedigrees were screened for mutations in adRP-associated genes through the Carver Laboratory or with APEX microarrays (385 or 414 variants arrays; Asper Ophthalmics). Because the adRP arrays included mutations in RHO and TOPORS, genes previously reported in PRD patients, 12,17 and in RDS, which was causative in one pericentral patient, 33 simplex and multiplex patients who were negative on arRP panels were also screened on the adRP arrays. All patients without a molecular diagnosis were screened for mutations in ABCA4 with APEX microarrays (496, 519, or 577 variants arrays; Asper Ophthalmics), 34 by Carver Laboratory or by Casey Eye Institute Molecular Testing Laboratory (Portland, OR, USA).…”

“…Another ad Norwegian pedigree showed pericentral disease in most of the affected family members and a TOPORS mutation was found to cosegregate with the disease. 12 Visual acuities ranged from normal to severely abnormal; ERGs were abnormal except in one patient who had a normal ERG. Both…”

“…11,16 Some autosomal dominant (ad) Norwegian families with affected members showing a pericentral pattern of disease had missense mutations in the RHO (rhodopsin) or TOPORS (topoisomerase I-binding arginine/serine rich) genes. 12,17 We identified a cohort of RD patients with a pericentral pattern of disease and then studied their phenotype by measures of visual function and retinal imaging. Gene screening was performed and one-half of the patients were found to have mutations in genes previously associated with ad or ar retinal degenerations.…”

“…2 Less common is a pattern of dysfunction that affects the retinal region surrounding the central few degrees, variably described as pericentral, perimacular, or paramacular retinal degeneration. 1,[3][4][5][6][7][8][9][10][11][12] It has been debated whether the retinal degenerations included under the diagnosis of pericentral retinal degeneration (PRD) are a distinct entity. 4,[13][14][15] Attempts have been made to identify the genetic cause of individuals with presumed autosomal recessive (ar) PRD but these have not been revealing.…”