Microtubule binding protein PACRG plays a role in regulating specific ciliary dyneins during microtubule sliding

Mizuno, Katsutoshi; Dymek, Erin E.; Smith, Elizabeth F.

doi:10.1002/cm.21340

Cited by 11 publications

(12 citation statements)

References 46 publications

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“…The authors declare no competing interests. Blanchon et al, (2012), Bragina et al, (2019), Brown et al, (2017), Davis et al, (2019), Gegg et al, (2014), Geremek et al, (2008), Ghandourah and Dell, (2018), Hjeij et al, (2014), Knowles et al, (2013), Li et al, (2019a), Lorenzetti et al, (2004), Meng et al, (2014), Merveille et al, (2011), Mira et al, (2004), Mizuno et al, (2016), Narasimhan et al, (2015), Onoufriadis et al, (2013), Perles et al, (2012), Reish et al, (2016), Sigg et al, (2017), Subaran et al, (2015), Sung et al, (2016), Ta-Shma et al, (2015, Vadnais et al, (2014), Wilson et al, (2010a), Wilson et al, (2010b), and Zhang et al, (2019). Sung, Y.H., Baek, I.-J., Kim, Y.H., Gho, Y.S., Oh, S.P., Lee, Y.J., and Lee, H.-W. (2016).…”

Section: Declaration Of Interestsmentioning

confidence: 99%

Structure of the Decorated Ciliary Doublet Microtubule

Stoyanova

Rademacher

et al. 2019

Cell

223

370

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Section: Declaration Of Interestsmentioning

confidence: 99%

Structure of the Decorated Ciliary Doublet Microtubule

Stoyanova

Rademacher

et al. 2019

Cell

223

370

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“…PACRG is a gene conserved across species ( Thumberger et al, 2012 ) that shares a bi-directional promoter with parkin ( PARK2 ) ( West et al, 2003 ). PACRG is affiliated with axonemal doublet microtubules, and contributes to the signaling pathway that controls dynein-driven microtubule sliding ( Thumberger et al, 2012 ; Mizuno, Dymek & Smith, 2016 ; Wilson et al, 2010 ; Ikeda, 2008 ). A SNV in PACRG was strongly associated with an increased risk of developing childhood asthma following early-life tobacco smoke exposure ( Scholtens et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, PTCH1 is differentially expressed in asthmatic compared to non-asthmatic horses following challenge ( Tessier et al, 2017 ), linking PACRG and an asthmatic response to environmental agents with the HH pathway. The PACRG protein associates with protofilaments ( Ikeda et al, 2007 ) of the ciliary axoneme ( Thumberger et al, 2012 ; Lechtreck et al, 2009 ; Dawe et al, 2005 ), has a role in ciliary morphogenesis and function ( Wilson et al, 2010 ) and is directly involved in ciliary motility through control of dynein-driven microtubule sliding ( Mizuno, Dymek & Smith, 2016 ). PACRG also has a variety of interacting partners such as microtubules, α- and β-tubulin and meiosis/spermiogenesis associated 1 (MEIG1) protein, heat shock protein (HSP) 70 and HSP 90 ( Ikeda, 2008 ; Li et al, 2015 ; Imai et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Sequence variant analysis of RNA sequences in severe equine asthma

Tessier

Côté

Bienzle

2018

PeerJ

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BackgroundSevere equine asthma is a chronic inflammatory disease of the lung in horses similar to low-Th2 late-onset asthma in humans. This study aimed to determine the utility of RNA-Seq to call gene sequence variants, and to identify sequence variants of potential relevance to the pathogenesis of asthma.MethodsRNA-Seq data were generated from endobronchial biopsies collected from six asthmatic and seven non-asthmatic horses before and after challenge (26 samples total). Sequences were aligned to the equine genome with Spliced Transcripts Alignment to Reference software. Read preparation for sequence variant calling was performed with Picard tools and Genome Analysis Toolkit (GATK). Sequence variants were called and filtered using GATK and Ensembl Variant Effect Predictor (VEP) tools, and two RNA-Seq predicted sequence variants were investigated with both PCR and Sanger sequencing. Supplementary analysis of novel sequence variant selection with VEP was based on a score of <0.01 predicted with Sorting Intolerant from Tolerant software, missense nature, location within the protein coding sequence and presence in all asthmatic individuals. For select variants, effect on protein function was assessed with Polymorphism Phenotyping 2 and screening for non-acceptable polymorphism 2 software. Sequences were aligned and 3D protein structures predicted with Geneious software. Difference in allele frequency between the groups was assessed using a Pearson’s Chi-squared test with Yates’ continuity correction, and difference in genotype frequency was calculated using the Fisher’s exact test for count data.ResultsRNA-Seq variant calling and filtering correctly identified substitution variants in PACRG and RTTN. Sanger sequencing confirmed that the PACRG substitution was appropriately identified in all 26 samples while the RTTN substitution was identified correctly in 24 of 26 samples. These variants of uncertain significance had substitutions that were predicted to result in loss of function and to be non-neutral. Amino acid substitutions projected no change of hydrophobicity and isoelectric point in PACRG, and a change in both for RTTN. For PACRG, no difference in allele frequency between the two groups was detected but a higher proportion of asthmatic horses had the altered RTTN allele compared to non-asthmatic animals.DiscussionRNA-Seq was sensitive and specific for calling gene sequence variants in this disease model. Even moderate coverage (<10–20 counts per million) yielded correct identification in 92% of samples, suggesting RNA-Seq may be suitable to detect sequence variants in low coverage samples. The impact of amino acid alterations in PACRG and RTTN proteins, and possible association of the sequence variants with asthma, is of uncertain significance, but their role in ciliary function may be of future interest.

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“…SNAP2, on the other hand, uses evolutionary, structural, solvent-PARK2)[63]. PACRG is affiliated with axonemal doublet microtubules, and contributes to the signaling pathway that controls dynein-driven microtubule sliding[62,[64][65][66]. A single nucleotide variant (SNV) in PACRG was strongly associated with an increased risk of developing childhood asthma following early-life tobacco smoke exposure[67].For the RTTN substitution variant, tryptophan is an aromatic, non-polar and hydrophobic amino acid often buried in hydrophobic cores, while arginine is a polar and positively charged amino acid often found on outside chains[68].…”

mentioning

confidence: 99%

Peer Review #1 of "Sequence variant analysis of RNA sequences in severe equine asthma (v0.2)"

2018

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Background. Severe equine asthma is a chronic inflammatory disease of the lung in horses similar to low-Th2 late-onset asthma in humans. This study aimed to determine the utility of RNA-Seq to call gene sequence variants, and to identify sequence variants or potential relevance to the pathogenesis of asthma. Methods. RNA-Seq data were generated from endobronchial biopsies collected from 6 asthmatic and 7 non-asthmatic horses before and after challenge (26 samples total). Sequences were aligned to the equine genome with Spliced Transcripts Alignment to Reference software. Read preparation for sequence variant calling was performed with Picard tools and Genome Analysis Toolkit (GATK). Sequence variants were called and filtered using GATK and Ensembl Variant Effect Predictor (VEP) tools, and two RNA-Seq predicted sequence variants were investigated with both PCR and Sanger sequencing. Supplementary analysis of novel sequence variant selection with VEP was based on a score of <0.01 predicted with Sorting Intolerant From Tolerant (SIFT) software, missense nature, location within the protein coding sequence and presence in all asthmatic individuals. For select variants, effect on protein function was assessed with Polymorphism Phenotyping (PolyPhen) 2 and Screening for Non-Acceptable Polymorphism (SNAP) 2 software. Sequences were aligned and 3D protein structures predicted with Geneious software. Difference in allele frequency between the groups was assessed using a Pearson's Chi-squared test with Yates' continuity correction, and difference in genotype frequency was calculated using the Fisher's exact test for count data. Results. RNA-Seq variant calling and filtering correctly identified substitution variants in PACRG and RTTN. Sanger sequencing confirmed that the PACRG substitution was appropriately identified in all 26 samples while the RTTN substitution was identified correctly in 24 of 26 samples. These variants of uncertain significance had substitutions that were predicted to result in loss of function and to be non-neutral. Amino acid substitutions projected no change of hydrophobicity and

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Microtubule binding protein PACRG plays a role in regulating specific ciliary dyneins during microtubule sliding

Cited by 11 publications

References 46 publications

Structure of the Decorated Ciliary Doublet Microtubule

Structure of the Decorated Ciliary Doublet Microtubule

Sequence variant analysis of RNA sequences in severe equine asthma

Peer Review #1 of "Sequence variant analysis of RNA sequences in severe equine asthma (v0.2)"

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