The Joubert Syndrome-associated Missense Mutation (V443D) in the Abelson-helper Integration Site 1 (AHI1) Protein Alters Its Localization and Protein-Protein Interactions

Tuz, Karina; Hsiao, Yi Chun; Juárez, Óscar; Shi, Bingxing; Harmon, Erin Y.; Phelps, Ian G.; Lennartz, Michelle R.; Glass, Ian A.; Doherty, Dan; Ferland, Russell J.

doi:10.1074/jbc.m112.420786

Cited by 32 publications

(41 citation statements)

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“…[28][29][30][31] The hypothesis that the missense variants in the WD40 domain do not completely abolish Jouberin function is further supported by our observation that cultured fibroblasts of patient A-II:1 (c.2174G>A and c.2258A>T) had no disrupted cilium formation, while Tuz et al showed that mutations in individuals with JBTS cause impaired ciliogenesis in patient's fibroblasts. 27 Additionally, we did not observe mislocalisation of either IFT-B (IFT88) or IFT-A (WDR19), a phenotype that was previously detected in other severe ciliopathies. [32][33][34][35] Moreover, on expression of the recombinant proteins, the RP-associated variants cause a decreased enrichment of Jouberin at the ciliary basal bodies compared with the wild-type protein.…”

Section: Discussionsupporting

confidence: 57%

“…The remaining nine missense (of which seven are located within the WD40 domain and three before the WD40 domain) were observed in a homozygous state in typical patients with JBTS, suggesting they have a severe effect on the Jouberin protein localisation and/or function, which has indeed been shown for the p.Val443Asp variant. 27 Using homology modelling, we show that of the seven Joubert-associated missense mutations, four have a predicted severe effect and two have a mild effect on the WD40 structure, while of the four non-syndromic retinal dystrophy missense mutations one has a severe, two have a mild and one has no clear effect on the WD40 structure. This indicates that most likely missense mutations detected in patients with Joubert syndrome have a more disruptive effect on the WD40 structure compared with the missense mutations detected in patients with non-syndromic RP.…”

Section: Discussionmentioning

confidence: 91%

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Missense mutations in the WD40 domain ofAHI1cause non-syndromic retinitis pigmentosa

et al. 2017

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BackgroundRecent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP).MethodsExome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient’s fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells.ResultsIn the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base.ConclusionsThis report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype–phenotype correlation for AHI1 mutation associated retinal ciliopathies.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 91%

Missense mutations in the WD40 domain ofAHI1cause non-syndromic retinitis pigmentosa

et al. 2017

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“…Western blotting was performed as previously described (Hsiao, et al, 2009, Tuz, et al, 2013). Briefly, protein concentrations were determined by bicinchoninic acid (BCA) assay based on protein standards (BCA Protein Assay kit, Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity

et al. 2015

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Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2’s seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final flurothyl rechallenge, ~85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.

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“…Taken together, the data suggest that a sodium gradient, produced by the Na ϩ -NQR complex, is essential for the infection and growth of C. trachomatis, likely sustaining the ability to produce energy through the aerobic metabolism. Moreover, the sodium gradient produced by Na ϩ -NQR can also be used by the cell to carry other essential homeostatic processes, such as pH regulation, through the Na ϩ -H ϩ antiporter NhaD (74), as well as nutrient transport, which seems to be carried mostly by Na ϩ -dependent transporters (12,75).…”

Section: Effect Of Ionophores On the Infection And Growth Of C Trachmentioning

confidence: 99%

Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation

Liang

Rosas‐Lemus²,

Patel

et al. 2018

Journal of Biological Chemistry

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is an obligate intracellular human pathogen responsible for the most prevalent sexually-transmitted infection in the world. For decades has been considered an "energy parasite" that relies entirely on the uptake of ATP from the host cell. The genomic data suggest that respiratory chain could produce a sodium gradient that may sustain the energetic demands required for its rapid multiplication. However, this mechanism awaits experimental confirmation. Moreover, the relationship of chlamydiae with the host cell, in particular its energy dependence, is not well understood. In this work, we are showing that has an active respiratory metabolism that seems to be coupled to the sodium-dependent synthesis of ATP. Moreover, our results show that the inhibition of mitochondrial ATP synthesis at an early stage decreases the rate of infection and the chlamydial inclusion size. In contrast, the inhibition of the chlamydial respiratory chain at mid-stage of the infection cycle decreases the inclusion size but has no effect on infection rate. Remarkably, the addition of monensin, a Na/H exchanger, completely halts the infection. Altogether, our data indicate that chlamydial development has a dynamic relationship with the mitochondrial metabolism of the host, in which the bacterium mostly depends on host ATP synthesis at an early stage, and at later stages it can sustain its own energy needs through the formation of a sodium gradient.

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The Joubert Syndrome-associated Missense Mutation (V443D) in the Abelson-helper Integration Site 1 (AHI1) Protein Alters Its Localization and Protein-Protein Interactions

Cited by 32 publications

References 41 publications

Missense mutations in the WD40 domain ofAHI1cause non-syndromic retinitis pigmentosa

Missense mutations in the WD40 domain ofAHI1cause non-syndromic retinitis pigmentosa

Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity

Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation

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