Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism

Jacobson, Samuel G.; Cideciyan, Artur V.; Alemán, Tomás S.; Sumaroka, Alexander; Román, Alejandro J.; Gardner, Leigh M.; Prosser, Haydn M.; Mishra, Monalisa; Bech-Hansen, N. Torben; Herrera, Waldo; Schwartz, Sharon; Liu, Xue Zhong; Kimberling, William J.; Steel, Karen P.; Williams, David S.

doi:10.1093/hmg/ddn140

Cited by 102 publications

(81 citation statements)

References 44 publications

(78 reference statements)

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“…In support, we show that the 3 proteins indeed interact. As with most Usher proteins, USH2A and GPR98 localize to the photoreceptor connecting cilium region, which plays a pivotal role in trafficking nascent proteins from inner to outer segment (15,16,23). Consistent with our genetic findings and protein interaction data, Pdzd7 is strongly localized in the basal part of the connecting cilium region in zebrafish and at the base of cilia in cultured RPE cells.…”

Section: Discussionsupporting

confidence: 85%

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Ebermann¹,

Phillips²,

Liebau³

et al. 2010

J. Clin. Invest.

204

167

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Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain-containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.

show abstract

Section: Discussionsupporting

confidence: 85%

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Ebermann¹,

Phillips²,

Liebau³

et al. 2010

J. Clin. Invest.

204

167

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“…In the absence of a reliable animal model, analysis of USH1B disease pathology is restricted to patients. Optical imaging and psychophysical testing of young USH1B patients revealed that photoreceptors are the first detectable site of disease ( Jacobson et al, 2008), highlighting the need to develop a gene replacement strategy that effectively targets both RPE and photoreceptors. Because the two allelic variants of human MYO7A are both relatively large, with coding sequences of 6534 and 6648 bp, respectively (Weil et al, 1996), treatment of USH1B will require a vector platform capable of delivering a relatively large cDNA.…”

mentioning

confidence: 99%

Dual Adeno-Associated Virus Vectors Result in EfficientIn VitroandIn VivoExpression of an Oversized Gene,MYO7A

Dyka

Boye²,

Chiodo³

et al. 2014

Human Gene Therapy Methods

107

125

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Usher syndrome 1B (USH1B) is a severe, autosomal recessive, deaf-blind disorder caused by mutations in myosin 7A (MYO7A). Patients are born profoundly deaf and exhibit progressive loss of vision starting in their first decade. MYO7A is expressed in human photoreceptors and retinal pigment epithelium, but disease pathology begins in photoreceptors, highlighting the need to develop a gene replacement strategy that effectively targets this cell type. For its safety and efficacy in clinical trials and ability to transduce postmitotic photoreceptors, we have focused on developing a clinically applicable adeno-associated virus (AAV) platform for delivering full-length MYO7A cDNA (*6.7 kb). Packaging of full-length MYO7A cDNA in AAV produces vectors with heterogeneous, fragmented genomes (''fAAV'') capable of reconstituting full-length cDNA postinfection. We previously showed that fAAV vectors effectively delivered full-length MYO7A in vitro and in vivo. However, fAAV vectors are relatively inefficient and their heterogeneous genomes preclude definitive characterization, a drawback for clinical translatability. The aim of this study was to overcome these limitations by creating dual-AAV-vector platforms for USH1B with defined genomes. Human MYO7A was cloned in AAV vector pairs, each containing genomes < 5 kb and intact inverted terminal repeats. One vector contained a promoter and 5¢ portion of the cDNA and the partner vector contained a 3¢ portion and polyadenylation signal. ''Simple overlap'' vectors share a central part of the MYO7A cDNA sequence. ''Trans-splicing'' and ''hybrid'' vectors utilize splice donor and acceptor sites with and without an additional central recombinogenic sequence, respectively. Vector pairs expressed full-length MYO7A in vitro and in vivo with equal or higher efficiency than fAAV, with a hybrid platform being most efficient. Importantly, analysis of MYO7A mRNA derived from each dual-vector platform revealed 100% fidelity to the predicted sequence. Our results suggest that dual AAV vectors with defined genetic payloads are a potential treatment option for USH1B.

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“…This suggestion is supported by a study of mice that contained mosaics of MYO7A-positive and MYO7A-null cells in their tissues. In these mice, the photoreceptor phenotype was demonstrated to be cell autonomous and not secondary to lack of MYO7A in the adjacent RPE (Jacobson et al 2008 ) .…”

Section: Myo7a -Mutant Micementioning

confidence: 94%

Gene Therapy Strategies for Usher Syndrome Type 1B

Williams¹,

Lopes²

2011

Retinal Degenerative Diseases

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Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism

Cited by 102 publications

References 44 publications

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Dual Adeno-Associated Virus Vectors Result in EfficientIn VitroandIn VivoExpression of an Oversized Gene,MYO7A

Gene Therapy Strategies for Usher Syndrome Type 1B

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