Nonhuman Primate Model of Oculocutaneous Albinism with
            <i>TYR</i>
            and
            <i>OCA2</i>
            Mutations

Wu, Kun; Lv, Ji‐Neng; Yang, Hui; Yang, Fengmei; Lin, Rui; Lin, Qiang; Shen, Ren‐Juan; Wang, Junbin; Duan, Wenhua; Hu, Min; Zhang, Jun; He, Zhanlong

doi:10.34133/2020/1658678

Cited by 10 publications

(11 citation statements)

References 70 publications

(91 reference statements)

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“…We also screened a cohort of hundreds of rhesus macaques, and six individuals were diagnosed with oculocutaneous albinism without fovea. 44 We further identified a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2. 44 The spontaneous, inherited retinal degeneration of NHP models is described in the literature, but they are too rare to meet research needs.…”

Section: Discussionmentioning

confidence: 84%

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Generation of Nonhuman Primate Model of Cone Dysfunction through In Situ AAV-Mediated CNGB3 Ablation

Lin

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Summary A major challenge to the development of therapies for human retinal degenerative diseases is the lack of an ideal preclinical model because of the physiological differences between humans and most model animals. Despite the successful generation of a primate model through germline knockout of a disease-causing gene, the major issues restricting modeling in nonhuman primates (NHPs) are their relatively long lifespan, lengthy gestation, and dominant pattern of singleton births. Herein, we generated three cynomolgus macaques with macular in situ knockout by subretinal delivery of an adeno-associated virus (AAV)-mediated CRISPR-Cas9 system targeting CNGB3 , the gene responsible for achromatopsia. The in vivo targeting efficiency of CRISPR-Cas9 was 12%–14%, as shown by both immunohistochemistry and single-cell transcriptomic analysis. Through clinical ophthalmic examinations, we observed a reduced response of electroretinogram in the central retina, which corresponds to a somatic disruption of CNGB3. In addition, we did not detect CRISPR-Cas9 residue in the heart, liver, spleen, kidney, brain, testis, or blood a year after administration. In conclusion, we successfully generated a NHP model of cone photoreceptor dysfunction in the central retina using an in situ CNGB3-knockout strategy.

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Section: Discussionmentioning

confidence: 84%

“… 44 We further identified a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2. 44 The spontaneous, inherited retinal degeneration of NHP models is described in the literature, but they are too rare to meet research needs. Hence, genetically engineered monkey models are especially sought after.…”

Section: Discussionmentioning

confidence: 84%

Generation of Nonhuman Primate Model of Cone Dysfunction through In Situ AAV-Mediated CNGB3 Ablation

Lin

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…Animal models of various types of OCA are well characterized and recapitulate pigmentation defects robustly, shedding light on the cellular nature of these defects ( OCA1A : Onojafe et al, 2011 ; Zhou et al, 2015 ; Wu et al, 2020 ; OCA2 : Rinchik et al., 1993 ; Ishikawa et al., 2015 ; Wu et al, 2020 ; OCA3 : Onojafe et al, 2018 ; OCA4 : Winkler et al., 2014 ; OCA6 : Yousaf et al., 2020 ; OA1 : Incerti et al, 2000 ). Most of these studies are focused on melanosome biogenesis defects in melanocytes and very few on RPE defects.…”

Section: Discussionmentioning

confidence: 99%

In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium

et al. 2022

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Oculocutaneous albinism (OCA) encompasses a set of autosomal recessive genetic conditions that affect pigmentation in the eye, skin, and hair. OCA patients display reduced best-corrected visual acuity, reduced to absent ocular pigmentation, abnormalities in fovea development, and/or abnormal decussation of optic nerve fibers. It has been hypothesized that improving eye pigmentation could prevent or rescue some of the vision defects. The goal of the present study was to develop an in vitro model for studying pigmentation defects in human retinal pigment epithelium (RPE). We developed a ''disease in a dish'' model for OCA1A and OCA2 types using induced pluripotent stem cells to generate RPE. The RPE is a monolayer of cells that are pigmented, polarized, and polygonal in shape, located between the neural retina and choroid, with an important role in vision. Here we show that RPE tissue derived in vitro from OCA patients recapitulates the pigmentation defects seen in albinism, while retaining the apical-basal polarity and normal polygonal morphology of the constituent RPE cells.

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“…These issues include the variability in disease onset and progression rate, incomplete penetrance, and high inter- and intra-familial genetic heterogeneity for Mendelian disorders, including OCA [ 17 , 18 ]. Recently, a rhesus macaque model of albinism revealed biallelic variants in both TYR and OCA2 that have been used to carry out foveal development studies and preclinical trials of new therapies for OCA [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Causes of Oculocutaneous Albinism in Pakistani Population

Sajid

Yousaf

Waryah

et al. 2021

Genes

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Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.

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Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations

Cited by 10 publications

References 70 publications

Generation of Nonhuman Primate Model of Cone Dysfunction through In Situ AAV-Mediated CNGB3 Ablation

Generation of Nonhuman Primate Model of Cone Dysfunction through In Situ AAV-Mediated CNGB3 Ablation

In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium

Genetic Causes of Oculocutaneous Albinism in Pakistani Population

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