Missense mutation of rhodopsin gene codon 15 found in Japanese autosomal dominant retinitis pigmentosa

Zhang

et al. 2017

Sci Rep

Retinitis pigmentosa (RP) is highly heterogeneous in both clinical and genetic fields. Accurate mutation screening is very beneficial in improving clinical diagnosis and gene-specific treatment of RP patients. The reason for the difficulties in genetic diagnosis of RP is that the ethnic-specific mutation databases that contain both clinical and genetic information are largely insufficient. In this study, we recruited 98 small Han Chinese families clinically diagnosed as RP, including of 22 dominant, 19 recessive, 52 sporadic, and five X-linked. We then used whole exome sequencing (WES) analysis to detect mutations in the genes known for RP in 101 samples from these 98 families. In total, we identified 57 potential pathogenic mutations in 40 of the 98 (41%) families in 22 known RP genes, including 45 novel mutations. We detected mutations in 13 of the 22 (59%) typical autosomal dominant families, 8 of the 19 (42%) typical autosomal recessive families, 16 of the 52 (31%) sporadic small families, and four of the five (80%) X-linked families. Our results extended the mutation spectrum of known RP genes in Han Chinese, thus making a contribution to RP gene diagnosis and the pathogenetic study of RP genes.

Section: Discussionsupporting

confidence: 84%

Mutation screening in genes known to be responsible for Retinitis Pigmentosa in 98 Small Han Chinese Families

Zhang

et al. 2017

Sci Rep

Journal of Biological Chemistry

“…We attribute these differences between the WT and T4R opsins to the positive charge at Arg 4 resulting from the mutation and not the subsequent lack of glycosylation at Asn 2 , as bovine deglycosylated Rho in our assays showed very similar properties to WT Rho. However, lack of glycosylation at Asn 15 may cause other cell biological problems, as a substitution of Ser for Asn (N15S) was identified in a patient with autosomal dominant RP (70,71). In the case of human N15S and dog T4R mutations, the degeneration occurs within distinctive topographic regions (sectorial RP) (22, 70 -72) that could be related to differences in light exposure.…”

Section: Discussionmentioning

confidence: 99%

A Naturally Occurring Mutation of the Opsin Gene (T4R) in Dogs Affects Glycosylation and Stability of the G Protein-coupled Receptor

Zhu

Jang

Jastrzębska

et al. 2004

Rho (rhodopsin; opsin plus 11-cis-retinal) is a prototypical G protein-coupled receptor responsible for the capture of a photon in retinal photoreceptor cells. A large number of mutations in the opsin gene associated with autosomal dominant retinitis pigmentosa have been identified. The naturally occurring T4R opsin mutation in the English mastiff dog leads to a progressive retinal degeneration that closely resembles human retinitis pigmentosa caused by the T4K mutation in the opsin gene. Using genetic approaches and biochemical assays, we explored the properties of the T4R mutant protein. Employing immunoaffinity-purified Rho from affected RHO T4R/T4R dog retina, we found that the mutation abolished glycosylation at Asn 2 , whereas glycosylation at Asn 15 was unaffected, and the mutant opsin localized normally to the rod outer segments. Moreover, we found that T4R Rho* lost its chromophore faster as measured by the decay of meta-rhodopsin II and that it was less resistant to heat denaturation. Detergent-solubilized T4R opsin regenerated poorly and interacted abnormally with the G protein transducin (G t ). Structurally, the mutation affected mainly the "plug" at the intradiscal (extracellular) side of Rho, which is possibly responsible for protecting the chromophore from the access of bulk water. The T4R mutation may represent a novel molecular mechanism of degeneration where the unliganded form of the mutant opsin exerts a detrimental effect by losing its structural integrity.

“…Although it only targeted exons with known mutations, the study failed to identify high frequency RP genes [11] . Another study of the Japanese RP population focused on the RP genes RHO [12] – [14] and EYS [15] , [16] , and found that EYS was a frequent arRP gene with a prevalence rate of 9% to 16% [15] , [16] . However, almost all reported EYS gene mutations in these studies have not been reported in Western populations suggesting that Japanese individuals have a different genetic background [15] , [16] .…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Analysis Identifies Frequent CNGA1 Mutations in Japanese Population with Autosomal Recessive Retinitis Pigmentosa

et al. 2014

ObjectiveThe purpose of this study was to investigate frequent disease-causing gene mutations in autosomal recessive retinitis pigmentosa (arRP) in the Japanese population.MethodsIn total, 99 Japanese patients with non-syndromic and unrelated arRP or sporadic RP (spRP) were recruited in this study and ophthalmic examinations were conducted for the diagnosis of RP. Among these patients, whole exome sequencing analysis of 30 RP patients and direct sequencing screening of all CNGA1 exons of the other 69 RP patients were performed.ResultsWhole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients), EYS (three patients) and SAG (one patient) in eight patients and potential disease-causing gene variants of USH2A (two patients), EYS (one patient), TULP1 (one patient) and C2orf71 (one patient) in five patients. Screening of an additional 69 arRP/spRP patients for the CNGA1 gene mutation revealed one patient with a homozygous mutation.ConclusionsThis is the first identification of CNGA1 mutations in arRP Japanese patients. The frequency of CNGA1 gene mutation was 5.1% (5/99 patients). CNGA1 mutations are one of the most frequent arRP-causing mutations in Japanese patients.