The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells

Kirschman, Lindsay T.; Kolandaivelu, Saravanan; Frederick, Jeanne M.; Dang, Loan; Goldberg, Andrew F.X.; Baehr, Wolfgang; Ramamurthy, Visvanathan

doi:10.1093/hmg/ddp571

Cited by 64 publications

(62 citation statements)

References 35 publications

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“…Our findings demonstrate a third distinction of PDE6: the requirement of a specialized photoreceptor-specific chaperone, AIPL1, for proper folding. This requirement was previously postulated for two reasons: the relative ease of heterologous expression of various PDEs other than PDE6 and the destabilization of PDE6 in mice lacking AIPL1 (14,15,40). Our data demonstrate that AIPL1 is an obligatory chaperone for PDE6, whereas P␥ acts as potent co-chaperone that markedly enhances production of the folded enzyme provided that AIPL1 is present.…”

Section: Discussionsupporting

confidence: 59%

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client

Gopalakrishna

Boyd

Yadav

et al. 2016

Journal of Biological Chemistry

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Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction cascade and is critical for the health of both rod and cone photoreceptors. Its dysfunction, caused by mutations in either the enzyme itself or AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1), leads to retinal diseases culminating in blindness. Progress in research on PDE6 and AIPL1 has been severely hampered by failure to express functional PDE6 in a heterologous expression system. Here, we demonstrated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of cone PDE6C in cultured cells. We further show that the AIPL1-mediated production of folded PDE6C is markedly elevated in the presence of the inhibitory P␥-subunit of PDE6. As illustrated in this study, a simple and sensitive system in which AIPL1 and P␥ are co-expressed with PDE6 represents an effective tool for probing structure-function relationships of AIPL1 and reliably establishing the pathogenicity of its variants.Cyclic nucleotide phosphodiesterases of the sixth family (PDE6) 2 are the key effectors in the visual transduction cascade in rod and cone photoreceptors. In the dark, activity of the PDE6 catalytic dimers is restrained by two tightly bound inhibitory ␥-subunits (P␥). This allows cGMP to maintain depolarizing "dark" current through a cGMP-gated channel in the photoreceptor plasma membrane. Photoexcitation leads to G-protein-mediated activation of PDE6 followed by a drop in cytoplasmic cGMP, channel closure, and propagation of an electrical signal to downstream retinal neurons (1, 2). In addition to being essential to photoreceptor physiology, PDE6 is critical to the health and survival of rods and cones. Malfunctions caused by mutations in genes that encode either PDE6 or its putative chaperone, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), lead to severe blinding retinal diseases.Mutations in the PDE6A, PDE6B, and PDE6G genes, which encode the catalytic PDE6AB subunits and P␥ of rod PDE6, respectively, are responsible for a significant proportion of cases of recessive retinitis pigmentosa (3-5) and can also lead to autosomal dominant congenital stationary night blindness (6). Mutations in their cone counterparts, PDE6C and PDE6H, cause autosomal recessive achromatopsia (7-10).PDE6 deficiency also appears to underlie one of the most severe forms of Leber congenital amaurosis (LCA type 4), a condition caused by mutations in the AIPL1 gene (11,12). LCA is an early onset inherited retinopathy and one of the main causes of blindness in children (13). The link between PDE6 and AIPL1 was discovered in studies of AIPL1 knock-out and knockdown mouse models, which revealed rapid severe retinal degeneration and a marked reduction in PDE6 protein levels and activity prior to the loss of photoreceptor cells (14, 15). Thus, the animal models recapitulated the hallmarks of LCA and suggested that AIPL1 is a potential chaperone of PDE6. This notion is consistent with the fact that AIPL1 contains an FK506-binding pro...

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Section: Discussionsupporting

confidence: 59%

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client

Gopalakrishna

Boyd

Yadav

et al. 2016

Journal of Biological Chemistry

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“…Imaging of stained retinal sections were performed at the WVU Microscope Imaging Facility with a Zeiss LSM 510 laser scanning confocal microscope using excitation wavelengths of 488, 543, and 633 nm. Primary antibodies used in this study were: G␣ transducin (G␣T1) polyclonal (Santa Cruz Biotechnology), cone transducin (G␣T2) polyclonal (Santa Cruz Biotechnology), blue-, and red/green-cone opsin polyclonal (Chemicon International), GC-E/F (David Garbers), rod PDE6␣␤␥ polyclonal (MOE, cytosignal), rod PDE6␣, PDE6␤, and PDE␥ subunit specific antibodies (ABR), cone PDE␥Ј (Vadim Arshavsky) and cone PDE6␣' polyclonal antibody (3184P) (19). All primary antibodies were used at 1:1,000 dilution and secondary antibodies at 1:2,000 dilution, unless noted otherwise.…”

Section: Methodsmentioning

confidence: 99%

Rod Phosphodiesterase-6 (PDE6) Catalytic Subunits Restore Cone Function in a Mouse Model Lacking Cone PDE6 Catalytic Subunit

Kolandaivelu

Chang

Ramamurthy

2011

Journal of Biological Chemistry

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Rod and cone photoreceptor neurons utilize discrete PDE6 enzymes that are crucial for phototransduction. Rod PDE6 is composed of heterodimeric catalytic subunits (␣␤), while the catalytic core of cone PDE6 (␣) is a homodimer. It is not known if variations between PDE6 subunits preclude rod PDE6 catalytic subunits from coupling to the cone phototransduction pathway. To study this issue, we generated a cone-dominated mouse model lacking cone PDE6 (Nrl ؊/؊ cpfl1). In this animal model, using several independent experimental approaches, we demonstrated the expression of rod PDE6 (␣␤) and the absence of cone PDE6 (␣) catalytic subunits. The rod PDE6 enzyme expressed in cone cells is active and contributes to the hydrolysis of cGMP in response to light. In addition, rod PDE6 expressed in cone cells couples to the light signaling pathway to produce S-cone responses. However, S-cone responses and light-dependent cGMP hydrolysis were eliminated when the ␤-subunit of rod PDE6 was removed (Nrl ؊/؊ cpfl1 rd). We conclude that either rod or cone PDE6 can effectively couple to the cone phototransduction pathway to mediate visual signaling. Interestingly, we also found that functional PDE6 is required for trafficking of M-opsin to cone outer segments.Vertebrate visual perception is mediated by two types of photoreceptor cells, rods, and cones (1-3). Rods mediate vision in dim light and respond to a single photon. In contrast, cones mediate vision in bright light, are less sensitive than rods to light, respond faster, and adapt to light stimuli over several orders of magnitude (1). Although the transduction mechanism used by both rods and cones to detect and respond to light are similar, the protein components that mediate the visual signaling are distinct (3). The differences between rod and cone responses are likely due to levels and variations in the protein transduction machinery (2, 3). Phototransduction is initiated when photoisomerized rhodopsin or cone opsin activates transducin, which in turn activates light-activated rod phosphodiesterase-6 (PDE6), 2 the effector of the cascade (2, 3). PDE6 hydrolyzes cGMP resulting in closure of cation channels and subsequent hyperpolarization of photoreceptor cell membranes (4). No differences in light-dependent signaling between rods and cones are observed at the level of opsin activation (5). In contrast, cell-specific transducin subunits contributes to altered signaling properties between rods and cones (6). However, this finding is contradicted by another study showing that rod and cone transducin are able to substitute for each other efficiently (7).The last step in the phototransduction cascade, the activation of PDE6 by transducin subunits is different between rods and cones. Apart from transducin, rods and cones contain distinct PDE6 subunits (4). Rod PDE6 exists as a heteromer with two catalytic subunits (␣␤) and two inhibitory (␥) subunits. Rod PDE6 is the only member of a vast family of PDE proteins that functions as a catalytic heterodimer. Cone PDE6 is composed of two i...

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“…cone-rod dystrophy vs. RP). In fact, this was the case for 2 of our patients who in spite of being initially included in the RP group, we identified to have a missense variant predicted as probably damaging in a gene linked with cone-rod dystrophy (AIPL1 gene) [29]. A subsequent clinical exploration of these 2 patients suggested a phenotype compatible with cone-rod dystrophy.…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, we were able to detect a probably damaging variant in the cone-rod-related gene AIPL1, p.Arg324Leu (rs150427474) [29], and a mutation in a regulatory region of the RP-related gene, C8orf37. Based on its exclusive presence in patient 49 and its absence both in 3 nonaffected first-degree family members and among the pool of 30 nonaffected individuals, we consider this rare regulatory variant a candidate in the pathogenesis of the IRD.…”

Section: Resultsmentioning

confidence: 99%

A Cost-Effective Mutation Screening Strategy for Inherited Retinal Dystrophies

Barandika

Irigoyen²,

Anasagasti³

et al. 2016

Ophthalmic Res

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Objective: We developed a simple, time- and cost-effective Excel-based genetic screening strategy for the diagnosis of inherited retinal dystrophies (IRD). Design: 76 patients diagnosed with IRD and 112 nonaffected family members, from 55 unrelated families, were included. DNA samples were analyzed using Axiom Exome Genotyping Array Plates (Affymetrix) that contain over 300,000 genetic variants, including more than 5,000 variants present in 181 genes involved in IRD. We used a simple Excel-based data mining strategy in order to screen IRD variants likely involved in the development of IRD. Results: A total of 5 relevant genetic variants were found in 5 IRD genes. Four variants were reported either as pathogenic or with a prediction of probably damaging, and 1 variant was reported to affect a regulatory region. These variants were present in 14 patients and in 11 carriers, in 10 unrelated families. Conclusion: Using our Excel-based data screening strategy, we were able to assign likely genetic diagnoses in a fast and cost-effective manner to over 18% of patients analyzed, with a comparable ratio of genetic findings to that reported with retina-specific arrays for about 1/5 of the cost. Our approach proved efficient in reducing costs and time for IRD diagnosis as a first tier genetic screening method.

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The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells

Cited by 64 publications

References 35 publications

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client

Rod Phosphodiesterase-6 (PDE6) Catalytic Subunits Restore Cone Function in a Mouse Model Lacking Cone PDE6 Catalytic Subunit

A Cost-Effective Mutation Screening Strategy for Inherited Retinal Dystrophies

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