Identification of a novel RHO heterozygous nonsense mutation in a Chinese family with autosomal dominant retinitis pigmentosa

Abstract

Background: To explore the molecular genetic cause of a four-generation autosomal dominant retinitis pigmentosa family in China.

Methods: Targeted region sequencing was performed to detect the potential mutation, and Sanger sequencing was used to validate the mutation. Multiple sequence alignment from different species was performed by CLUSTALW. The structures of wild-type and the mutant RHO were modeled by Swiss-Model Server and shown using a PyMOL Molecular Graphic system.

Results: A novel heterozygous nonsense mutation (c.1015 A > T, p.Lys339Ter, p.K339X) within RHO, which cosegregated with retinitis pigmentosa phenotype was detected in this family. Bioinformatics analysis showed the mutation was located in a highly conserved region, and the mutation was predicted to be pathogenic.

Conclusions: We identified a novel heterozygous nonsense mutation of RHO gene in a Chinese family with retinitis pigmentosa by target region sequencing and our bioinformatics analysis indicated that the mutation is pathogenic. Our results can broaden the spectrum of RHO gene mutation and enrich the phenotype-genotype correlation of retinitis pigmentosa.

Keywords: RHO gene; Retinitis pigmentosa; Rhodopsin.

Fig. 1

Pedigree map of the family. The arrow indicates the proband. Squares and circles symbolize males and females, respectively. Black and white denotes affected and unaffected individuals, respectively

Fig. 2

Fundus photographs of the proband. Note the attenuated arterioles, waxy pallor of the optic disc, atrophy of the choroid and diffuse bone-spicule pigmentation in both eyes

Fig. 3

Sanger sequencing of RHO and bioinformatics analysis of the mutation. A Sanger sequencing of RHO detected a c.1015A > T transversion in affected patients which caused the replacement of a wild-type Lysine with stop codon at codon 339. B Multiple-sequence alignments of RHO in various species showed codon 339 was located within a highly conserved region

Fig. 4

Structure model of rhodopsin-arrestin complex. Left: C-terminus of rhodopsin was shown in sticks, and the phosphorylation codes (D330, E332, T336, S338, E341) were highlighted. Arrestin was shown in vacuum electrostatics, blue area represents positive charge while red area represents negative charge. Normally, arrestin ‘reads’ phosphorylation codes of rhodopsin through code-sensing pockets. Right: K339X mutation of RHO produced a truncated protein and interfered the arrestin recruitment