Clinical features of X linked juvenile retinoschisis in Chinese families associated with novel mutations in the RS1 gene

Abstract

Purpose: To describe the clinical phenotype of X linked juvenile retinoschisis (XLRS) in 12 Chinese families with 11 different mutations in the XLRS1 (RS1) gene.

Methods: Complete ophthalmic examinations were carried out in 29 affected males (12 probands), 38 heterozygous females carriers, and 100 controls. The coding regions of the RS1 gene that encodes retinoschisin were amplified by polymerase chain reaction and directly sequenced.

Results: Of the 29 male participants, 28 (96.6%) displayed typical foveal schisis. Eleven different RS1 mutations were identified in 12 families; four of these mutations, two frameshift mutations (26 del T of exon 1 and 488 del G of exon 5), and two missense mutations (Asp145His and Arg156Gly) of exon 5, had not been previously described. One non-disease-related polymorphism (NSP): 576C to T (Pro192Pro) change was also newly reported herein. We compared genotypes and observed more severe clinical features in families with the following mutations: frameshift mutation (26 del T) of exon 1, the splice donor site mutation (IVS1+2T to C),or Arg102Gln, Arg209His, and Arg213Gln mutations.

Conclusions: Severe XLRS phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations. The wide variability in the phenotype in Chinese patients with XLRS and different mutations in the RS1 gene is described. Identification of mutations in the RS1 gene and expanded information on clinical manifestations will facilitate early diagnosis, appropriate early therapy, and genetic counseling regarding the prognosis of XLRS.

Figure 1

Pedigrees of families with X linked juvenile retinoschisis and identified mutations in the RS1 gene. Dark-shaded boxes represent family members with X-linked juvenile retinoschisis, while light-shaded boxes and circles mark those with nondisease-related polymorphisms. Circles with a dot denote obligate carriers. Arrows point to probands. Slashed circles or boxes are deceased family members.

Figure 2

Fundus photographs and DNA sequence in Patient 20 of Family 20. Fundus of left eye (A) showing severe foveal and peripheral retinoschisis with tractional retinal detachment and proliferative vitreoretinopathy. DNA sequencing examination revealed Arg209His mutation -626G->A of exon 6 in normal control (B) and Patient 20 (C).

Figure 3

Fundus photographs and DNA sequencing in Patient 60 of Family 60. Fundus of right eye (A, B) showing cystoid-like maculopathy and peripheral retinoschisis. The left eye underwent vitrectomy with comobined sclera buckling because of retinal detachment and vitreous hemorrhage (C). Peripheral retinoschisis was found during the operation. DNA sequencing showed missense mutation -433G->C, Asp 145 His of exon 5 in normal control (D) and Patient 60 (E).

Figure 4

Fundus photographs, optical coherence tomography images, and DNA sequencing in Proband 140, and his grandfather, (Patient 142) of Family 140. The fundi of right (A) and left (B) eyes of Patient 140 showing cystoid-like maculopathies and golden-yellow reflex. Optical coherence tomography images of his right (C) and left (D) eyes revealed splitting had occured in the inner retina around the fovea. A normal fundus appearance (E) can be seen in his grandfather (Patient 142) with the same mutation. When ompared with the normal control (F), DNA sequencing showed the Arg200Cys mutation (598C->T) of exon 6 in Proband 140 (G).