ab3c769d4ae777b71ff9c35df89a6395 pmc_31936765.pdf 63d1ea5df85ca6165cac37ecfe8aeb0120e5ff68 pmc_31936765.pdf fc910b4cf28da5d490014839e5edc6d26b63e47051a38e49fae734f5cf1eb4c1 pmc_31936765.pdf Title: The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis Subject: The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%–60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS. Keywords: IL22RA2; IL-22 binding protein isoform; mutation; signal peptide; multiple sclerosis; autoimmune Author: Paloma Gómez-Fernández, Aitzkoa Lopez de Lapuente Portilla, Ianire Astobiza, Jorge Mena, Andoni Urtasun, Vivian Altmann, Fuencisla Matesanz, David Otaegui, Elena Urcelay, Alfredo Antigüedad, Sunny Malhotra, Xavier Montalban, Tamara Castillo-Triviño, Laura Espino-Paisán, Orhan Aktas, Mathias Buttmann, Andrew Chan, Bertrand Fontaine, Pierre-Antoine Gourraud, Michael Hecker, Sabine Hoffjan, Christian Kubisch, Tania Kümpfel, Felix Luessi, Uwe K. Zettl, Frauke Zipp, Iraide Alloza, Manuel Comabella, Christina M. 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no 597 0 PKCOGM+Calibri CID TrueType Identity-H yes yes yes 622 0 PKDBHK+Arial,Bold CID TrueType Identity-H yes yes yes 623 0 PKDBIL+Calibri,Bold CID TrueType Identity-H yes yes yes 624 0 PKBCKL+PalatinoLinotype TrueType WinAnsi yes yes no 625 0 PKBDAL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 626 0 PKBDBN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 627 0 PKCOGM+Calibri CID TrueType Identity-H yes yes yes 685 0 PKDBHK+Arial,Bold CID TrueType Identity-H yes yes yes 686 0 PKDBIL+Calibri,Bold CID TrueType Identity-H yes yes yes 687 0 PKBCKL+PalatinoLinotype TrueType WinAnsi yes yes no 688 0 PKBDAL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 689 0 PKBDBN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 690 0 PKBCKL+PalatinoLinotype TrueType WinAnsi yes yes no 753 0 PKBDAL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 754 0 PKBDBN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 755 0 PKBCKL+PalatinoLinotype TrueType WinAnsi yes yes no 770 0 PKBDAL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 771 0 PKBDBN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 772 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:46:41 CEST RepresentationInformation: pmc_31936765.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:43:50 CEST Size: 7905804 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 8 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: きちぴづひどちぬびぜ〴ぜ〰ちのつぜ〴ぜ〰きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはのぴひはぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こづぬづっぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぇづのはぴべばどのでぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰ぁののはぴちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰びどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰がづふぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはぜ〴ぜ〰ごひちのびどぴどはのぜ〴ぜ〰ぃはつづつぜ〴ぜ〰ぢべぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰はのぜ〴ぜ〰こどでのちぬぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: ぐちぴどづのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰ぃはのぴひはぬびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こづぬづっぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぇづのはぴべばどのでぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰ぁののはぴちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰びどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰がづふぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはぜ〴ぜ〰ごひちのびどぴどはのぜ〴ぜ〰ぃはつづつぜ〴ぜ〰ぢべぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰はのぜ〴ぜ〰こどでのちぬぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こづぬづっぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぇづのはぴべばどのでぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰ぁののはぴちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰びどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰がづふぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはぜ〴ぜ〰ごひちのびどぴどはのぜ〴ぜ〰ぃはつづつぜ〴ぜ〰ぢべぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰はのぜ〴ぜ〰こどでのちぬぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰うふのっぴどはのちぬぜ〴ぜ〰ぁののはぴちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰びどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰がづふぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはぜ〴ぜ〰ごひちのびどぴどはのぜ〴ぜ〰ぃはつづつぜ〴ぜ〰ぢべぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰はのぜ〴ぜ〰こどでのちぬぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: うふのっぴどはのちぬぜ〴ぜ〰ぁののはぴちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰こぎぐびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰びどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰がづふぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはぜ〴ぜ〰ごひちのびどぴどはのぜ〴ぜ〰ぃはつづつぜ〴ぜ〰ぢべぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰はのぜ〴ぜ〰こどでのちぬぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぉのぜ〴ぜ〰びどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰がづふぜ〴ぜ〰ぴはぜ〴ぜ〰ぐひはぜ〴ぜ〰ごひちのびどぴどはのぜ〴ぜ〰ぃはつづつぜ〴ぜ〰ぢべぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰はのぜ〴ぜ〰こどでのちぬぜ〴ぜ〰ぐづばぴどつづぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㘩‾㸊⡜㌷㙜㌷㝜〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ば〮がづふ〱〶ぐひはぜ〴ぜ〰きふぴちでづのづびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ごとひづづぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㜩‾㸊⡜㌷㙜㌷㝜〰ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぁびびづびびねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぅててづっぴぜ〴ぜ〰はてぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰はのぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐぜ〴ぜ〰ぉびはてはひねびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㠩‾㸊⡜㌷㙜㌷㝜〰げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづばぬちっづねづのぴぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰こぐぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉが〱〷ぁぜ〴ぜ〰こぐぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㤩‾㸊⡜㌷㙜㌷㝜〰うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: うぬはぷぜ〴ぜ〰ぃべぴはねづぴひべぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰っはつどのでぜ〴ぜ〰こぎぐぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰どびぜ〴ぜ〰ぁびびはっどちぴづつぜ〴ぜ〰ぷどぴとぜ〴ぜ〰げどびにぜ〴ぜ〰てはひぜ〴ぜ〰きふぬぴどばぬづぜ〴ぜ〰こっぬづひはびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰こどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰いづっひづちびづびぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〱〬ぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉが〭〲〲あぐど〳ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: ごとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰っはつどのでぜ〴ぜ〰こぎぐぜ〴ぜ〰ひび〲〸〳〸〵〶〹〲ぜ〴ぜ〰どびぜ〴ぜ〰ぁびびはっどちぴづつぜ〴ぜ〰ぷどぴとぜ〴ぜ〰げどびにぜ〴ぜ〰てはひぜ〴ぜ〰きふぬぴどばぬづぜ〴ぜ〰こっぬづひはびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぉのぜ〴ぜ〰こどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰いづっひづちびづびぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〱〬ぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉが〭〲〲あぐど〳ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぉのぜ〴ぜ〰こどぬどっはぜ〴ぜ〰ぁのちぬべびどびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰ごとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰いづっひづちびづびぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〱〬ぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉが〭〲〲あぐど〳ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ごとづぜ〴ぜ〰ば〮がづふ〱〶ぐひはぜ〴ぜ〰ざちひどちのぴぜ〴ぜ〰いづっひづちびづびぜ〴ぜ〰こづっひづぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぉが〭〲〲あぐど〱〬ぜ〴ぜ〰ぉが〭〲〲あぐど〲ぜ〴ぜ〰ちのつぜ〴ぜ〰ぉが〭〲〲あぐど〳ぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⹁⸩‾㸊⠩਼㰠⽓ 䝯呯 䐠⡦楧畲攮捡灴楯渮ㄸ Item: Title: Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: TGMEOR+Rpcxr FontSubset: true FirstChar: 169 LastChar: 174 FontDescriptor: FontName: TGMEOR+Rpcxr Flags: Symbolic 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