scholarly journals An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease

2018 ◽  
Author(s):  
Suvi Mäkeläinen ◽  
Marta Gòdia ◽  
Minas Hellsand ◽  
Agnese Viluma ◽  
Daniela Hahn ◽  
...  
Keyword(s):  
Visual Impairment ◽  
Retinal Degeneration ◽  
Autosomal Recessive ◽  
Retinal Pigment ◽  
Clinical Signs ◽  
Premature Stop Codon ◽  
Large Animal ◽  
Loss Of Function ◽  
Stargardt Disease ◽  
Abca4 Gene

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in humans and dogs. Currently, no standard treatment is available but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs1395) was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium. The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.

scholarly journals Ocular safety assessment of sodium iodate in cynomolgus monkeys

2017 ◽  
Vol 1 ◽  
pp. 239784731769637 ◽  
Author(s):  
Chang-Ning Liu ◽  
Qinghai Peng ◽  
David W Yates ◽  
Wenhu Huang ◽  
Heather Devantier ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Cell Function ◽  
Retinal Pigment ◽  
Vehicle Control ◽  
Retinal Toxicity ◽  
Circulating Microrna ◽  
Large Animal ◽  
Sodium Iodate ◽  
Cynomolgus Monkeys ◽  
Functional Changes

Although sodium iodate (NaIO3)-induced retinal injury model has been widely used in rodents, its application in large animal species has encountered variation in retinal toxicity. NaIO3 induced retinal degeneration and functional changes in sheep, but not in swine. In monkeys, administration of NaIO3 via a carotid artery affected only the cell function of ipsilateral retinal pigment epithelium. The aim of the present study was to identify the dosage and route of NaIO3 administration resulting in morphologic and functional retinal changes in cynomolgus monkeys. Separate groups of animals received NaIO3 intravenously in three different dosing paradigms. Vehicle control animals received phosphate-buffered saline. At selected time points following dosing, flash electroretinograms (ERGs) were recorded followed by necropsy. The eyes were examined microscopically post-necropsy and the levels of circulating microRNA-183 cluster were evaluated in the blood samples collected on days 1, 4, and 5 postdose. A statistically significant reduction in both scotopic a-wave and scotopic and photopic b-wave signals ( p < 0.05) were observed between the ERG signals acquired from NaIO3-treated and vehicle control animals, coupled with time-dependent elevations in plasma miR-183 cluster. Mild to moderate retinal degeneration was observed in the outer layer of the retina, which correlated well with the functional and clinical observations. There were no statistically significant differences in scotopic oscillatory potentials. These findings suggest that intravenous injection of sublethal NaIO3 markedly damaged the cone and rod photoreceptors both functionally and morphologically, and plasma miR-183 reflected the retinal toxicity in those animals with moderate retinal damage.

scholarly journals Laurence-Moon-Bardet-Biedl Syndrome: A case report

2019 ◽  
Vol 59 (6) ◽  
pp. 349-52
Author(s):  
Md. Mozammel Haque ◽  
Kamrunnaher Shultana ◽  
Tahmina Binte Matin ◽  
Md. Shohidul Islam Khan ◽  
Abdullah Al Baki
Keyword(s):  
Mental Retardation ◽  
Case Report ◽  
Autosomal Recessive ◽  
Genetic Disorder ◽  
Retinal Pigment ◽  
Clinical Signs ◽  
Mental Deficiency ◽  
Cone Dystrophy ◽  
Anal Atresia ◽  
Bardet Biedl Syndrome

Laurence-Moon-Bardet-Beidl syndrome is a rare ciliopathic and pleiotropic human autosomal recessive genetic disorder.1 In 1886, Laurence and Moon explained a case of a 7-year-old female with rod-cone dystrophy, hypogenitalism, mental retardation, obesity, and polydactyly. In 1920, Bardet described a 4-year-old female patient presented with rod-cone dystrophy, obesity, polydactyly (11 toes), and mental retardation.1 Two years after Bardet’s report, Biedl highlighted the complete scenario of clinical signs which includes skull abnormalities, anal atresia, mental deficiency, and gastrointestinal conflicts.1 Since these discoveries, symptoms such as obesity, hypogonadism, retinal pigment defects, psychological hindrance, and polydactylismin in several conditions as combinations, frequently in children with normal parents (cousin marriages) has been termed as Laurence-Moon-Bardet-Biedl syndrome (LMBBS).1

scholarly journals Gene augmentation and read-through rescue channelopathy in an iPSC-RPE model of congenital blindness

2018 ◽  
Author(s):  
Pawan K. Shahi ◽  
Dalton Hermans ◽  
Divya Sinha ◽  
Simran Brar ◽  
Hannah Moulton ◽  
...  
Keyword(s):  
Visual Information ◽  
Autosomal Recessive ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Loss Of Function ◽  
Normal Morphology ◽  
Rpe Cells ◽  
Or Gene ◽  
Inwardly Rectifying ◽  
Leber’S Congenital Amaurosis

PurposeMutations in the KCNJ13 gene are known to cause Leber’s Congenital Amaurosis (LCA16), an inherited pediatric blindness. KCNJ13 gene encodes the Kir7.1 subunit protein which acts as a tetrameric inwardly rectifying potassium ion channel in the retinal pigment epithelium to maintain ionic homeostasis thereby allowing photoreceptors to encode visual information. We sought to determine if genetic approaches might be effective in treating blindness due to mutations in KCNJ13.MethodsWe developed patient-derived hiPSC-RPE carrying an autosomal recessive nonsense mutation in the KCNJ13 gene (c.158G>A, p.Trp53*). We performed biochemical and electrophysiology assays of Kir7.1 function. Both small molecule read-through drug and gene-therapy approaches were tested using this disease-in-a-dish approach.ResultsWe found that the LCA16 hiPSC-RPE had normal morphology but did not express a functional Kir7.1 channel and was unable to demonstrate normal physiology. Following read-through drug treatment, the LCA16 hiPSC cells were hyperpolarized by 30 mV and Kir7.1 current was restored. Similarly, loss-of-function of Kir7.1 channel was circumvented by lentiviral gene delivery to the hiPSC-RPE cells. In either approach, Kir7.1 protein was expressing normally with restoration of membrane potential and Kir7.1 current.ConclusionLoss-of-function mutation in Kir7.1 is a cause of LCA. Using either read-through therapy or gene augmentation, we rescued Kir7.1 channel function in patient-derived iPSC-RPE cells via a precision medicine approach.

scholarly journals Case series of Stargardt's disease: Our experience

2016 ◽  
Vol 7 (2) ◽  
pp. 147
Author(s):  
Syed Abdul Wadud ◽  
Muntasir Bin Shahid ◽  
Sumon Afroz
Keyword(s):  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Autosomal Recessive ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Case Series ◽  
Macular Dystrophy ◽  
Stargardt Disease ◽  
Bull’S Eye Maculopathy ◽  
Bull's Eye

<p>Stargardt disease is the most common form of juvenile macular degeneration. Clinically, it is characterized by pisciform flecks at lhe level of the retinal pigment epithelium and a bull's-eye maculopathy. Inheritance is usually autosomal recessive, although dominantly inherited case have been described. Both sexes are affected equally. We reported here three cases of Stargardt's macular dystrophy, who are siblings and daughters of non consanguineous parents. In case-1,2 and 3 we found the typical presentation with almost same findings.</p>

scholarly journals Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality

2020 ◽  
pp. jmedgenet-2020-106873
Author(s):  
Marilena Elpidorou ◽  
Sunayna Best ◽  
James A Poulter ◽  
Verity Hartill ◽  
Emma Hobson ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Stop Codon ◽  
Neurodevelopmental Disorder ◽  
Premature Stop Codon ◽  
Homozygous Deletion ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Functional Characterisation ◽  
Mitochondrial Functions ◽  
And Function

BackgroundThe HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype.Methods and resultsWe ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA.ConclusionThis study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders.

scholarly journals Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to cilia-related abnormal cardiac left–right patterning

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Yuan Zhang ◽  
Weicheng Chen ◽  
Weijia Zeng ◽  
Zhouping Lu ◽  
Xiangyu Zhou
Keyword(s):  
Stop Codon ◽  
Retinal Pigment ◽  
Premature Stop Codon ◽  
Nuclear Pore ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Tem Analysis ◽  
Protein Levels ◽  
Biallelic Mutations

AbstractDefective left–right (LR) organization involving abnormalities in cilia ultrastructure causes laterality disorders including situs inversus (SI) and heterotaxy (Htx) with the prevalence approximately 1/10,000 births. In this study, we describe two unrelated family trios with abnormal cardiac LR patterning. Through whole-exome sequencing (WES), we identified compound heterozygous mutations (c.805-1G >C; p. Ile269GlnfsTer8/c.1117dupA; p.Thr373AsnfsTer19) (c.29T>C; p.Ile10Thr/c.356A>G; p.His119Arg) of NEK3, encoding a NIMA (never in mitosis A)-related kinase, in two affected individuals, respectively. Protein levels of NEK3 were abrogated in Patient-1 with biallelic loss-of function (LoF) NEK3 mutations that causes premature stop codon. Subsequence transcriptome analysis revealed that NNMT (nicotinamide N-methyltransferase) and SIRT2 (sirtuin2) was upregulated by NEK3 knockdown in human retinal pigment epithelial (RPE) cells in vitro, which associates α-tubulin deacetylation by western blot and immunofluorescence. Transmission electron microscopy (TEM) analysis further identified defective ciliary ultrastructure in Patient-1. Furthermore, inner ring components of nuclear pore complex (NPC) including nucleoporin (NUP)205, NUP188, and NUP155 were significantly downregulated in NEK3-silenced cells. In conclusion, we identified biallelic mutations of NEK3 predispose individual to abnormal cardiac left–right patterning via SIRT2-mediated α-tubulin deacetylation and downregulation of inner ring nucleoporins. Our study suggested that NEK3 could be a candidate gene for human ciliopathies.

scholarly journals Stargardt Disease Caused by a Rare Combination of Double Homozygous Mutations

Medicina ◽  
2013 ◽  
Vol 49 (8) ◽  
pp. 60
Author(s):  
Danielius Serapinas ◽  
Viltautė Obrikytė ◽  
Raimundas Sakalauskas
Keyword(s):  
Autosomal Recessive ◽  
Severe Disease ◽  
Disease Phenotype ◽  
Stargardt Disease ◽  
Recessive Mutations ◽  
Rare Combination ◽  
Abca4 Gene ◽  
Genetic Mechanisms ◽  
Blurry Vision ◽  
Autosomal Recessive Pattern

Stargardt disease is a juvenile macular degeneration most often inherited in an autosomal recessive pattern, characterized by decreased vision in the first 2 decades of life. This report presents a clinical case of Stargardt disease: a 10-year-old female patient complained of blurry vision, and in a 4-year period, her visual acuity was reduced from OD=0.3 and OS=0.3 to OD=0.08 and OS=0.1, respectively. A genetic analysis revealed a rare combination of 2 homozygous recessive mutations in the ABCA4 gene, which caused Stargardt disease. The presence of different genetic mechanisms leading to a severe disease phenotype can challenge molecular geneticists, ophthalmologists, and genetic counselors.

ABCA4-Associated Stargardt Disease

2020 ◽  
Vol 237 (03) ◽  
pp. 267-274 ◽  
Author(s):  
Mubeen Khan ◽  
Frans P.M. Cremers
Keyword(s):  
Autosomal Recessive ◽  
Late Onset ◽  
Human Kidney ◽  
In Vitro Assays ◽  
Kidney Cells ◽  
Stargardt Disease ◽  
Abca4 Gene ◽  
Transcriptomics Data ◽  
Degree Of Severity

AbstractAutosomal recessive Stargardt disease (STGD1) is associated with variants in the ABCA4 gene. The phenotypes range from early-onset STGD1, that clinically resembles severe cone-rod dystrophy, to intermediate STGD1 and late-onset STGD1. These different phenotypes can be correlated with different combinations of ABCA4 variants which can be classified according to their degree of severity. A significant fraction of STGD1 cases, particularly late-onset STGD1 cases, were shown to carry only a single ABCA4 variant. A frequent coding variant (p.Asn1868Ile) was recently identified which – in combination with a severe ABCA4 variant – is generally associated with late-onset STGD1. In addition, an increasing number of rare deep-intronic variants have been found and some of these are also associated with late-onset STGD1. The effect of these and other variants on ABCA4 RNA was tested using in vitro assays in human kidney cells using specially designed midigenes. With stem cells and photoreceptor progenitor cells derived from patient skin or blood cells, retina-specific splice defects can be assessed. With expert clinical examination to distinguish STGD1 cases from other maculopathies, as well as in-depth genomics and transcriptomics data, it is now possible to identify both mutant ABCA4 alleles in > 95% of cases.

scholarly journals Clinical and Genetic Correlations of Inherital Retinal Disease with Mutations in the ABCA4 Gene by Patients of the Russian Population

2021 ◽  
Vol 18 (4) ◽  
pp. 897-907
Author(s):  
I. V. Zolnikova ◽  
V. V. Kadyshev ◽  
A. V. Marakhonov ◽  
A. B. Chernyak ◽  
S. V. Milash ◽  
...  
Keyword(s):  
Molecular Genetics ◽  
Russian Federation ◽  
Genetic Correlations ◽  
Clinical Signs ◽  
Russian Population ◽  
Homozygous Mutation ◽  
Stargardt Disease ◽  
Mild Phenotype ◽  
Full Field ◽  
Abca4 Gene

Aim: to study genotype-phenotype correlations in patients with inherited retinal diseases with mutations in ABCA4 gene in Russian Federation.Patients and methods. 21 patients from Russian population aged from 7 to 51 years old (mean age 20 ± 11 years with best-corrected visual acuity from 0,02 to 0,6 (0,14 ± 0,11) with ABCA4-associated retinopathy, verified by molecular genetics methods. All patients besides standard ophthalmic examination and photodocumentation were performed Spectral-Domain OCT and fundus autofluorescence on Spectralis ®HRA+OCT (Heidelberg Engineering, Germany). Full-field electroretinogram (ERG), 30-Hz flicker ERG and macular chromatic ERG (MERG) to red stimulus were recorded on electroretinographic system MBN (MBN, Russia). (Russia) Molecular genetic studies were performed using Next Generation Sequencing (NGS) and Sandger direct sequencing. Results: In ABCA4-associated Stargardt disease 1 type (STGD1) genotype [p.L541P, p.A1038V] of «frequent» mutations was revealed in 9 patients, in 2 cases in was associated another “frequent” mutation p.G1961E. In 4 patients with genotype [p.L541P, p.A1038V] “severe” phenotype of Stargardt disease was found: with large defect of the ellipsoid zone and large zone of central reduced autofluorescence, severely subnormal macular ERG (MERG) to red stimulus and subnormal 30 Hz flicker and full-field maximal ERG. In one patient with these mutations in homozygous state ABCA4-associated cone-rod dystrophy (CORD3, clinically looking alike secondary retinal dystrophy is diagnosed. In 2 patients with genotype [p.L541P, p.A1038V] and mutation p.G1961E was found mild phenotype. One patient with homozygous mutation p.R653C autosomal recessive ABCA4-associated retinitis pigmentosa (RP19) was diagnosed. Clinical picture and autofluorescence were polymorphic in all patients.Conclusions. Our study with ophthalmological, molecular genetics and instrumental methods widens the spectrum of clinical signs of inherited eye diseases associated with mutations in АВСА4 gene, widens the spectrum mutations in Russian Federation and reveals clinicо-genetic genotype-phenotype correlations.

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