f29ea39ee3904502b87ab89fdd6cfa27 pmc_33801522.pdf 001ad8603f59707bf162551d0bf7c72762ef3bae pmc_33801522.pdf cf947e05791aad2d07c0e4455b8d7f093b4d28f576440b93b33617677f3b4cfd pmc_33801522.pdf Title: Expanding the -III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration Subject: (1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by -III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical spinocerebellar ataxia type 5 (SCA5). (2) Methods: In-depth phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modeling and protein expression. An extensive review of the literature was conducted in order to better characterize the SPTBN2-associated NPCA. (3) Results: Patients exhibited an NPCA with hypotonia, developmental delay, cerebellar syndrome, and cognitive deficits. Both probands presented with progressive global cerebellar volume loss in consecutive cerebral magnetic resonance imaging studies, characterized by decreasing midsagittal vermis relative diameter measurements. Cortical hyperintensities were observed on fluid-attenuated inversion recovery (FLAIR) images, suggesting a neurodegenerative process. Each patient carried a novel de novo SPTBN2 substitution: c.193A > G (p.K65E) or c.764A > G (p.D255G). Modeling and protein expression revealed that both mutations might be deleterious. (4) Conclusions: The reported findings contribute to a better understanding of the SPTBN2-associated phenotype. The mutations may preclude proper structural organization of the actin spectrin-based membrane skeleton, which, in turn, is responsible for the underlying disease mechanism. Keywords: SPTBN2 gene; -III spectrin; non-progressive congenital ataxia; neurodegeneration Author: Paula Sancho, Amparo Andrés-Bordería, Nerea Gorría-Redondo, Katia Llano, Dolores Martínez-Rubio, María Eugenia Yoldi-Petri, Luba Blumkin, Pablo Rodríguez de la Fuente, Fernando Gil-Ortiz, Leonor Fernández-Murga, Ana Sánchez-Monteagudo, Vincenzo Lupo, Belén Pérez-Dueñas, Carmen Espinós and Sergio Aguilera-Albesa Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Mar 4 04:39:52 2021 CET ModDate: Thu Mar 11 01:26:38 2021 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2837462 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 HHFREY+EURM7 Type 1 Builtin yes yes no 15 0 HKBJPQ+VnURWPalladioL Type 1 Custom yes yes no 19 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 23 0 TSDWCD+URWPalladioL-Ital Type 1 Custom yes yes no 27 0 QPGVVF+URWPalladioL-Bold Type 1 Custom yes yes no 32 0 YXHSCL+URWPalladioL-Roma Type 1 Custom yes yes no 36 0 ZYYJXI+EURB10 Type 1 Builtin yes yes no 40 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 48 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 73 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 77 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 81 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 93 0 IKCDDP+Symbol Type 1C Custom yes yes yes 100 0 IKCCEN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 105 0 IKCCEO+PalatinoLinotype CID TrueType Identity-H yes yes yes 108 0 IKCCEP+PalatinoLinotype TrueType WinAnsi yes yes no 114 0 IKCCFB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 117 0 IKCCPA+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 120 0 IKCCEN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 133 0 IKCCEP+PalatinoLinotype TrueType WinAnsi yes yes no 136 0 IKCCFB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 139 0 IKCCPA+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 142 0 IKCCEN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 152 0 IKCCEO+PalatinoLinotype CID TrueType Identity-H yes yes yes 155 0 IKCCEP+PalatinoLinotype TrueType WinAnsi yes yes no 161 0 IKCCFB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 164 0 IKCCPA+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 167 0 IKCCEN+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 179 0 IKCCEO+PalatinoLinotype CID TrueType Identity-H yes yes yes 182 0 IKCCEP+PalatinoLinotype TrueType WinAnsi yes yes no 188 0 IKCCFB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 191 0 IKCCPA+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 194 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:25:28 CEST RepresentationInformation: pmc_33801522.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:09:25 CEST Size: 2837462 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 411 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Clinical, Neuroimaging, and Genetic Findings Destination: subsection.2.1 Item: Title: Modeling of the SPTBN2 p.K65E and p.D255G Mutations Destination: subsection.2.2 Item: Title: Expression Analysis and Subcellular Location Studies Destination: subsection.2.3 Item: Title: Phenotype to Genotype Correlations Destination: subsection.2.4 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Patients: Clinical and Neuroimaging Assessment Destination: subsection.4.1 Item: Title: Genetics and Bioinformatics Destination: subsection.4.2 Item: Title: Conservation Analysis and Structural Modeling Destination: subsection.4.3 Item: Title: Protein Expression Destination: subsection.4.4 Item: Title: References Destination: subsection.4.4 Info: Title: Expanding the -III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration Author: Paula Sancho, Amparo Andrés-Bordería, Nerea Gorría-Redondo, Katia Llano, Dolores Martínez-Rubio, María Eugenia Yoldi-Petri, Luba Blumkin, Pablo Rodríguez de la Fuente, Fernando Gil-Ortiz, Leonor Fernández-Murga, Ana Sánchez-Monteagudo, Vincenzo Lupo, Belén Pérez-Dueñas, Carmen Espinós and Sergio Aguilera-Albesa Subject: (1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by -III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical spinocerebellar ataxia type 5 (SCA5). (2) Methods: In-depth phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modeling and protein expression. An extensive review of the literature was conducted in order to better characterize the SPTBN2-associated NPCA. (3) Results: Patients exhibited an NPCA with hypotonia, developmental delay, cerebellar syndrome, and cognitive deficits. Both probands presented with progressive global cerebellar volume loss in consecutive cerebral magnetic resonance imaging studies, characterized by decreasing midsagittal vermis relative diameter measurements. Cortical hyperintensities were observed on fluid-attenuated inversion recovery (FLAIR) images, suggesting a neurodegenerative process. Each patient carried a novel de novo SPTBN2 substitution: c.193A > G (p.K65E) or c.764A > G (p.D255G). Modeling and protein expression revealed that both mutations might be deleterious. (4) Conclusions: The reported findings contribute to a better understanding of the SPTBN2-associated phenotype. The mutations may preclude proper structural organization of the actin spectrin-based membrane skeleton, which, in turn, is responsible for the underlying disease mechanism. 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