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PMID:20440071

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Citation

Ebermann, I, Phillips, JB, Liebau, MC, Koenekoop, RK, Schermer, B, Lopez, I, Schäfer, E, Roux, AF, Dafinger, C, Bernd, A, Zrenner, E, Claustres, M, Blanco, B, Nürnberg, G, Nürnberg, P, Ruland, R, Westerfield, M, Benzing, T and Bolz, HJ (2010) PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J. Clin. Invest. 120:1812-23

Abstract

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.

Links

PubMed PMC2877930 Online version:10.1172/JCI39715

Keywords

Frameshift Mutation; Genotype; Hearing Loss/genetics; Homozygote; Humans; Male; Mutation; Phenotype; Receptors, G-Protein-Coupled/genetics; Retinitis Pigmentosa/genetics; Siblings; Syndrome; Usher Syndromes/genetics; Usher Syndromes/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A0R4IEP0

involved_in

GO:0060119: inner ear receptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IEP0

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IEP0

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-5,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IEP0

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-4,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IUM9

involved_in

GO:0060119: inner ear receptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IUM9

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IUM9

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-5,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A0R4IUM9

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-4,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:A0A2R8QIG1

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-4,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:D6BNA9

involved_in

GO:0060119: inner ear receptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:D6BNA9

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:D6BNA9

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-5,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:D6BNA9

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-4,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:F1QLV2

involved_in

GO:0060119: inner ear receptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:F1QLV2

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:F1QLV2

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-5,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:F1QLV2

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-4,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

HUMAN:USH2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H5P4

F

Seeded From UniProt

complete

DANRE:Q1MTD2

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-4,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

DANRE:AGRV1

involved_in

GO:0042462: eye photoreceptor cell development

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100617-5,ZFIN:ZDB-MRPHLNO-100624-9

P

Seeded From UniProt

complete

HUMAN:AGRV1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H5P4

F

Seeded From UniProt

complete

HUMAN:PDZD7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8WXG9

F

Seeded From UniProt

complete

HUMAN:PDZD7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75445

F

Seeded From UniProt

complete

HUMAN:PDZD7

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PDZD7

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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