PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family.

Download Full-text

Stargardt and Fundus Flavimaculatus; Current and Developing Treatments

Güncel Retina Dergisi (Current Retina Journal) ◽

10.37783/crj-0259 ◽

2021 ◽

pp. 190-200

Keyword(s):

Treatment Options ◽

Unmet Need ◽

Macular Dystrophy ◽

Stargardt Disease ◽

Need For Treatment ◽

Complement Inhibitors ◽

Abca4 Gene ◽

Hereditary Retinal Degeneration ◽

Pigment Epithelial Cells ◽

Fundus Flavimaculatus

Stargardt macular dystrophy is a hereditary retinal degeneration that lacks effective treatment options. The pathophysiology of the disease is still not fully understood. While there are currently no available treatments for Stargardt disease, there are many categories of therapeutics under investigation to fulfill this unmet need for treatment. These include investigational visual cycle modulators, complement inhibitors, ABCA4 gene therapy, and subretinal transplantation of stem cell-derived retina pigment epithelial cells. Further trials are warranted to assess efficacy and safety in humans. In this review, the treatments investigated for the Stargardt disease are explained.

Download Full-text

Discovering the genetic factors in eye disease

Impact ◽

10.21820/23987073.2018.3.68 ◽

2018 ◽

Vol 2018 (3) ◽

pp. 68-71

Author(s):

Takeshi Iwata

Keyword(s):

Visual Impairment ◽

Gene Mutations ◽

Eye Diseases ◽

World Health ◽

Eye Disease ◽

Genetic Mutations ◽

Macular Dystrophy ◽

Retinal Diseases ◽

Number Of Patients ◽

The World

Eye disease is an increasing problem, exacerbated by ageing populations in most countries. The National Eye Institute in the USA predicts that the cases of age-related macular degeneration (AMD) and glaucoma around the world will double by 2050. According to the World Health Organisation, these two diseases account for six per cent of all cases of visual impairment and blindness globally. Visual impairment affects quality of life and productivity and is therefore an important area of research. Professor Takeshi Iwata's laboratory is making ground-breaking discoveries in the specialist area of genetically-influenced retinal diseases. Most eye diseases are partly due to genetics, but the influence of a person's genotype is more profound in hereditary diseases such as retinitis pigmentosa and macular dystrophy. Specific genotypes are less influential, but play a role in AMD and glaucoma. The Iwata laboratory investigates AMD, glaucoma and 36 hereditary retinal diseases, to determine the genetic mutations that cause or predispose a patient towards developing disease. Iwata says: 'Our goal is to develop therapies for retinal eye diseases based on fundamental research into their molecular mechanisms.' Determining the genetic mutations behind each disease is the first step to realising this goal. As many of the hereditary retinal diseases are rare, collaboration is very important to the laboratory's work. To collect samples from a large number of patients, Iwata explains: 'We founded the Japan Eye Genetics Consortium (JEGC), a group comprising 30 ophthalmology departments throughout Japan.' Clinicians enter patients' phenotype information into a national genotype-phenotype database and send saliva or blood samples to the Iwata laboratory for gene analysis. Iwata explains: 'Following analysis, we upload whole exome and genome analysis results to the database to share amongst the collaborators.' The JEGC is already yielding important results. 80 per cent of families studied were found to have previously unidentified mutations. Functional analysis is underway to characterise each of these gene mutations in detail. Over 1366 family pedigrees have been collected, and the consortium aims to gather 5000 in total. In 2014, a more ambitious consortium was launched. The aim of the Asian Eye Genetics Consortium (AEGC), Iwata explains, is: 'to identify all the gene mutations responsible for hereditary eye diseases in the Asian population.' Over 150 scientists from 20 countries have been brought together through the consortium.

Download Full-text

Inherited retinal diseases in patients with ABCA4 gene mutations

Vestnik oftal mologii ◽

10.17116/oftalma201813404168 ◽

2018 ◽

Vol 134 (4) ◽

pp. 68 ◽

Cited By ~ 1

Author(s):

N. L. Sheremet ◽

I. G. Grushke ◽

N. V. Zhorzholadze ◽

A. S. Tanas ◽

V. V. Strelnikov

Keyword(s):

Gene Mutations ◽

Retinal Diseases ◽

Abca4 Gene

Download Full-text

Contribution of Genetic and Environmental Risk Factors in a Juvenile Idiopathic Arthritis Large Family With SERPINA1 Gene Mutations

10.21203/rs.3.rs-616020/v1 ◽

2021 ◽

Author(s):

Cyprian Popescu

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Gene Mutations ◽

Large Family ◽

Carrier Status ◽

Multiplex Family ◽

Serpina1 Gene ◽

Pathogenic Variants ◽

Whole Exome ◽

Genetic And Environmental Factors ◽

Underlying Mechanisms

Abstract Objectives Although the underlying mechanisms and mediators of arthritis in juvenile idiopathic arthritis (JIA) are not well understood, accumulated evidence supports the mixt role of genetic and environmental factors. Few reports of multiplex families with JIA were published until now. The aim of this study was to identify new genetic or environmental associations concerning the patients of a kindred with juvenile idiopathic arthritis and psoriatic features (JIAPs). Methods Here, we characterized an extended multiplex family of 5 patients with juvenile idiopathic arthritis and psoriatic features (PsA) at the clinical and genetic level, using whole exome sequencing. Results We did not confirm in our family the linkage with the genetic factors already described that might be associated with increase susceptibility to JIA. We found a carrier status of siblings who inherited a pathogenic allele of the SERPINA1 gene from their mother who herself has two heterozygous pathogenic variants in the SERPINA1 gene. Conclusions Our data showed that JIA results from pleiotropic effects of environmental background with an only minor monogenic contribution. Even that a monogenetic factor could not be proved, some genetic factor as SERPINA1 mutations which can sensitize for psoriatic arthritis development seems to be involved. Further investigation must be done to prove whether SERPINA1 mutations may have a potential JIA causality.

Download Full-text

Chapter-075 Central Areolar Choroidal Dystrophy and North Carolina Macular Dystrophy

Mastering Advanced Surface Ablation Techniques ◽

10.5005/jp/books/10490_75 ◽

2008 ◽

pp. 819-824

Author(s):

Sandeep Saxena

Keyword(s):

North Carolina ◽

Macular Dystrophy ◽

Central Areolar Choroidal Dystrophy

Download Full-text

Late onset is common in best macular dystrophy associated with VMD 2 gene mutations☆

Journal of End-to-End-testing ◽

10.1016/j.endend.2005.04.006 ◽

2005 ◽

Vol 32 (44) ◽

pp. e1-e9

Author(s):

A RENNER

Keyword(s):

Late Onset ◽

Gene Mutations ◽

Macular Dystrophy

Download Full-text

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

International Journal of Molecular Sciences ◽

10.3390/ijms21103430 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3430

Author(s):

Aneta Ścieżyńska ◽

Marta Soszyńska ◽

Michał Komorowski ◽

Anna Podgórska ◽

Natalia Krześniak ◽

...

Keyword(s):

Molecular Analysis ◽

Splice Site ◽

Human Hair ◽

Gene Mutations ◽

Hair Follicles ◽

Cdna Sequencing ◽

Stargardt Disease ◽

Protein Levels ◽

Abca4 Gene ◽

Functional Consequences

ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

Download Full-text

Study on the relationship between the pathogenic mutations of SLC26A4 and CT phenotypes of inner ear in patient with sensorineural hearing loss

Bioscience Reports ◽

10.1042/bsr20182241 ◽

2019 ◽

Vol 39 (3) ◽

Author(s):

Lihua Wu ◽

Yunliang Liu ◽

Jianman Wu ◽

Sheng Chen ◽

Shupin Tang ◽

...

Keyword(s):

Hearing Loss ◽

Ct Scan ◽

Inner Ear ◽

Gene Mutations ◽

Pathogenic Mutation ◽

Vestibular Aqueduct ◽

Slc26a4 Gene ◽

Pathogenic Mutations ◽

Inner Ear Malformation ◽

Single Allele

Abstract To investigate the possible association of pathogenic mutations of SLC26A4 and computerized tomography (CT) phenotypes of inner ear, and explore the feasibility of using the method of gene sequence analysis. A total of 155 patients with bilateral hearing loss carrying SLC26A4 gene mutations were further subjected to high-resolution temporal bone CT and thyroid B ultrasound tests. The potential relationship between the pathogenic mutations of gene and the CT phenotypes were analyzed. As a result, 65 patients (41.9%, 65/155) carried SLC26A4 gene mutations, and 27 cases were detected with pathogenic mutations of SLC26A4 where IVS7-2A>G (55.6%, 15/27) was the most common pathogenic mutation. Amongst them, 19 patients carrying bi-allelic SLC26A4 mutations were all confirmed to have inner ear malformation by CT scan including four cases of enlarged vestibular aqueduct (EVA) and 15 cases of Mondini dysplasia (MD). However, there was only one in eight cases of single allele pathogenic mutation who was confirmed to have EVA by CT scan. Further, only one patient with EVA was confirmed to be slightly higher of total T3 than normal by thyroid ultrasound scan and thyroid hormone assays. These findings suggested that CT detection and SLC26A4 gene detection are efficient methods to diagnose EVA, which can complement each other. Also, the bi-allelic pathogenic mutations of SLC26A4 are more likely to induce inner ear malformation than single allele pathogenic mutation.

Download Full-text