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The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1.

ABSTRACT: Mutations in the aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) gene have been found in patients with Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. To determine the normal function of AIPL1 and to better understand how mutations in this gene cause disease, we performed a yeast two-hybrid screen to identify AIPL1-interacting proteins in the retina. One of the identified interacting proteins corresponds to NUB1 (NEDD8 Ultimate Buster 1), which is thought to control many biological events, especially cell cycle progression, by downregulating NEDD8 expression. The AIPL1-NUB1 interaction was verified by co-immunoprecipitation studies in Y79 retinoblastoma cells, demonstrating that this interaction occurs within cells that share a number of features with retinal progenitor cells. Furthermore, we examined the localization of the AIPL1 protein within developing and adult retinas, and found that AIPL1 is present in the developing photoreceptor layer of the human retina and within the photoreceptors of the adult retina. Similar to AIPL1, NUB1 is also expressed in the developing and adult retina. Therefore, it is possible that the early-onset form of retinal degeneration seen in LCA patients with AIPL1 mutations may be due to a defect in the regulation of cell cycle progression during photoreceptor maturation. These data raise the possibility that AIPL1 is important for appropriate photoreceptor formation during development and/or survival following differentiation.

SUBMITTER: Akey DT

PROVIDER: S-EPMC2585502 | biostudies-literature | 2002 Oct

REPOSITORIES: biostudies-literature

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The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1.

Akey Dayna T DT Zhu Xuemei X Dyer Michael M Li Aimin A Sorensen Adam A Blackshaw Seth S Fukuda-Kamitani Taeko T Daiger Stephen P SP Craft Cheryl M CM Kamitani Tetsu T Sohocki Melanie M MM

Human molecular genetics 20021001 22

Mutations in the aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) gene have been found in patients with Leber congenital amaurosis (LCA), a severe, early-onset form of retinal degeneration. To determine the normal function of AIPL1 and to better understand how mutations in this gene cause disease, we performed a yeast two-hybrid screen to identify AIPL1-interacting proteins in the retina. One of the identified interacting proteins corresponds to NUB1 (NEDD8 Ultimate Buster 1), which ...[more]

PMID: 12374762

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Project description:BackgroundThe reduced cost and improved efficiency of whole genome sequencing (WGS) is drastically improving the development of cats as biomedical models. Persian cats are models for Leber's congenital amaurosis (LCA), the most severe and earliest onset form of visual impairment in humans. Cats with innocuous breed-defining traits, such as a bobbed tail, can also be models for somite segmentation and vertebral column development.MethodsThe first WGS in cats was conducted on a trio segregating for LCA and the bobbed tail abnormality. Variants were identified using FreeBayes and effects predicted using SnpEff. Variants within a known haplotype block for cat LCA and specific candidate genes for both phenotypes were prioritized by the predicted variant effect on the proteins and concordant segregation within the trio. The efficiency of WGS of a single trio of domestic cats was evaluated.ResultsA stop gain was identified at position c.577C > T in cat AIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified in HES7. The variants segregated concordantly in a Persian - Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for the AIPL1 variant, defining an allelic frequency in only Persian -related breeds of 1.15%. A sub-set of cats was genotyped for the HES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The cat AIPL1 variant would have been considered a high priority variant for evaluation, regardless of a priori knowledge from previous genetic studies.ConclusionsThis study represents the first effort of the 99 Lives Cat Genome Sequencing Initiative to identify disease--causing variants in the domestic cat using WGS. The current cat reference assembly is efficient for gene and variant identification. However, as the feline variant database improves, development of cats as biomedical models for human disease will be more efficient, providing an alternative, large animal model for drug and gene therapy trials. Undiagnosed human patients with early-onset blindness should be screened for this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.

Dataset Information

The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1.

Publications

The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1.

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