Toward an elucidation of the molecular genetics of inherited retinal degenerations

Farrar, G. Jane; Carrigan, Matthew; Dockery, Adrian; Millington‐Ward, Sophia; Palfi, Arpad; Chadderton, Naomi; Humphries, Marian M.; Kiang, Anna‐Sophia; Kenna, Paul F.; Humphries, Pete

doi:10.1093/hmg/ddx185

Cited by 76 publications

(82 citation statements)

References 65 publications

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“…(including primary open angle and primary angle closure types), and both wet and dry forms of age-related macular degeneration. We focused on ~200 genes for which association has been demonstrated by rare highly penetrant mutations or by GWAS studies (Farrar et al, 2017;Graham et al, 2018;MacGregor et al, 2018;Wiggs and Pasquale, 2017;Zeitz et al, 2015).…”

Section: Cell Type Specific Expression Of Human Retinal Disease Genesmentioning

confidence: 99%

“…We assembled lists of genome-wide associated study genes for prominent retinal diseases that cause blindness -primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), cone-rod dystrophy (CRD), retinitis pigmentosa (Leferink et al), congenital stationary night blindness (CSNB), age-related macular degeneration (Springelkamp et al) and diabetic macular edema (DME) from (Farrar et al, 2017;Fritsche et al, 2016;Graham et al, 2018;MacGregor et al, 2018;Wiggs and Pasquale, 2017;Zeitz et al, 2015).…”

Section: Evaluating Cell-type Specific Expression Of Disease Associatmentioning

confidence: 99%

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Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

Peng

Shekhar

Yan

et al. 2018

Preprint

133

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High acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible model organisms lack a fovea, its specialized function and dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate and validate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >65 cell types match between the two regions, but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved, but that projection neuron types and programs diverge, despite conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 6 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species. $00&;789: 4789:

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Section: Cell Type Specific Expression Of Human Retinal Disease Genesmentioning

confidence: 99%

Section: Evaluating Cell-type Specific Expression Of Disease Associatmentioning

confidence: 99%

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

Peng

Shekhar

Yan

et al. 2018

Preprint

133

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“…More than 200 genes are known to be implicated in retinal degeneration (73). Except retinal pigment epithelium 65 (RPE65) gene therapy (74), no causative treatments are available to date.…”

Section: Discussionmentioning

confidence: 99%

Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration

et al. 2019

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We previously reported that inactivation of the transmembrane taurine transporter (TauT or solute carrier 6a6) causes early retinal degeneration in mice. Compatible with taurine's indispensability for cell volume homeostasis, protein stabilization, cytoprotection, antioxidation, and immuno‐ and neuromodulation, mice develop multisystemic dysfunctions (hearing loss; liver fibrosis; and behavioral, heart, and skeletal muscle abnormalities) later on. Here, by genetic, cell biologic, in vivo 1H–magnetic resonance spectroscopy and molecular dynamics simulation studies, we conducted in‐depth characterization of a novel disorder: human TAUT deficiency. Loss of TAUT function due to a homozygous missense mutation caused panretinal degeneration in 2 brothers. TAUTp.A78E still localized in the plasma membrane but is predicted to impact structural stabilization. 3H‐taurine uptake by peripheral blood mononuclear cells was reduced by 95%, and taurine levels were severely reduced in plasma, skeletal muscle, and brain. Extraocular dysfunctions were not yet detected, but significantly increased urinary excretion of 8‐oxo‐7,8‐dihydroguanosine indicated generally enhanced (yet clinically unapparent) oxidative stress and RNA oxidation, warranting continuous broad surveillance.—Preising, M. N., Görg, B., Friedburg, C., Qvartskhava, N., Budde, B. S., Bonus, M., Toliat, M. R., Pfleger, C., Altmüller, J., Herebian, D., Beyer, M., Zöllner, H. J., Wittsack, H.‐J., Schaper, J., Klee, D., Zechner, U., Nürnberg, P., Schipper, J., Schnitzler, A., Gohlke, H., Lorenz, B., Häussinger, D., Bolz, H. J. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J. 33, 11507–11527 (2019). http://www.fasebj.org

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“…Our laboratory's studies of inbred communities have been conducive to the discovery of disease‐causing mutations underlying numerous inherited syndromes affecting different biologic systems, including specific progress in identifying heritable eye diseases, and more specifically––inherited retinal diseases (IRDs) (Gradstein et al, ; Mordechai et al, ; Perez et al, ; Yogev et al, ). To date, as many as 260 genes have been identified as causing IRDs, including Bardet–Biedl syndrome (BBS), chorioretinal atrophy, cone‐rod dystrophy, Leber congenital amaurosis, Usher syndrome, and most commonly retinitis pigmentosa (RP) (Farrar et al, ; SP Daiger, Greenberg, & Christoffels, ). In fact, according to the Retinal Information Network “RetNet” (http://www.sph.uth.tmc.edu/RetNet/), more than 70 genes have been identified as causing monogenic RP (Farrar et al, ) in various modes of heredity: autosomal recessive, autosomal dominant, and X‐linked (SP Daiger et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…To date, as many as 260 genes have been identified as causing IRDs, including Bardet–Biedl syndrome (BBS), chorioretinal atrophy, cone‐rod dystrophy, Leber congenital amaurosis, Usher syndrome, and most commonly retinitis pigmentosa (RP) (Farrar et al, ; SP Daiger, Greenberg, & Christoffels, ). In fact, according to the Retinal Information Network “RetNet” (http://www.sph.uth.tmc.edu/RetNet/), more than 70 genes have been identified as causing monogenic RP (Farrar et al, ) in various modes of heredity: autosomal recessive, autosomal dominant, and X‐linked (SP Daiger et al, ).…”

Section: Introductionmentioning

confidence: 99%

Combined CNV, haplotyping and whole exome sequencing enable identification of two distinct novel EYS mutations causing RP in a single inbred tribe

Wormser

Gradstein

Kadar

et al. 2018

American J of Med Genetics Pt A

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Whole exome sequencing (WES) has become routine in clinical practice, especially in studies of recessive hereditary diseases in inbred consanguineous families, where homozygosity of a founder mutation is assumed. Multiple members of two consanguineous families of a single Bedouin tribe were diagnosed with apparently autosomal recessive/pseudo-dominant retinitis pigmentosa (RP). Affected individuals exhibited severe visual impairment with nyctalopia, marked constriction of visual fields, markedly reduced and delayed responses on electro-retinography (ERG) and eventual loss of central vision. Combined copy-number variant (CNV) analysis, haplotype reconstruction and WES of the kindred identified two distinct novel mutations in EYS (RP25): a p.(W1817*) nonsense mutation (identified through WES) and a large deletion encompassing 9 of the 43 exons, that was missed by WES and was identified through microarray CNV analysis. Segregation analysis of both mutations demonstrated that all affected individuals were either homozygous for one of the mutations, or compound heterozygous for both. The two mutations are predicted to cause loss of function of the encoded protein and were not present in screening of 200 ethnically-matched controls. Our findings of two distinct mutations in the same gene in a single inbred kindred, identified only through combined WES and microarray CNV analysis, highlight the limitations of either CNV or WES alone, as the heterozygous deletion had normal WES read-depth values. Moreover, they demonstrate pitfalls in homozygosity mapping for disease-causing variant identification in inbred communities.

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Toward an elucidation of the molecular genetics of inherited retinal degenerations

Cited by 76 publications

References 65 publications

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina

Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration

Combined CNV, haplotyping and whole exome sequencing enable identification of two distinct novel EYS mutations causing RP in a single inbred tribe

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