Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants
To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impac...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Tokatly Latzer, Itay [verfasserIn] Roullet, Jean-Baptiste [verfasserIn] Cesaro, Samuele [verfasserIn] DiBacco, Melissa L. [verfasserIn] Arning, Erland [verfasserIn] Rotenberg, Alexander [verfasserIn] Lee, Henry H. C. [verfasserIn] Opladen, Thomas - 1974- [verfasserIn] Jeltsch, Kathrin - 1981- [verfasserIn] García-Cazorla, Àngels [verfasserIn] Juliá-Palacios, Natalia [verfasserIn] Gibson, K. Michael [verfasserIn] Bertoldi, Mariarita [verfasserIn] Pearl, Phillip L. - 1958- [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
14 November 2023 |
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| Anmerkung: |
Gesehen am 23.04.2024 |
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| Umfang: |
22 |
| Übergeordnetes Werk: |
Enthalten in: Human genetics - Berlin : Springer, 1964, 142(2023), 12, Seite 1755-1776 |
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| Übergeordnetes Werk: |
volume:142 ; year:2023 ; number:12 ; pages:1755-1776 ; extent:22 |
| Links: |
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| DOI / URN: |
10.1007/s00439-023-02613-6 |
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| Katalog-ID: |
1886542252 |
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| 100 | 1 | |a Tokatly Latzer, Itay |e verfasserin |0 (DE-588)1327031213 |0 (DE-627)1886543038 |4 aut | |
| 245 | 1 | 0 | |a Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants |c Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl |
| 264 | 1 | |c 14 November 2023 | |
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| 500 | |a Gesehen am 23.04.2024 | ||
| 520 | |a To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. | ||
| 700 | 1 | |a Roullet, Jean-Baptiste |e verfasserin |4 aut | |
| 700 | 1 | |a Cesaro, Samuele |e verfasserin |4 aut | |
| 700 | 1 | |a DiBacco, Melissa L. |e verfasserin |4 aut | |
| 700 | 1 | |a Arning, Erland |e verfasserin |4 aut | |
| 700 | 1 | |a Rotenberg, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Henry H. C. |e verfasserin |4 aut | |
| 700 | 1 | |a Opladen, Thomas |d 1974- |e verfasserin |0 (DE-588)124489656 |0 (DE-627)642820481 |0 (DE-576)335321291 |4 aut | |
| 700 | 1 | |a Jeltsch, Kathrin |d 1981- |e verfasserin |0 (DE-588)144019353 |0 (DE-627)656815140 |0 (DE-576)340367520 |4 aut | |
| 700 | 1 | |a García-Cazorla, Àngels |e verfasserin |4 aut | |
| 700 | 1 | |a Juliá-Palacios, Natalia |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, K. Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Bertoldi, Mariarita |e verfasserin |4 aut | |
| 700 | 1 | |a Pearl, Phillip L. |d 1958- |e verfasserin |0 (DE-588)1219985287 |0 (DE-627)1736103814 |4 aut | |
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10.1007/s00439-023-02613-6 doi (DE-627)1886542252 (DE-599)KXP1886542252 (OCoLC)1443669417 DE-627 ger DE-627 rda eng Tokatly Latzer, Itay verfasserin (DE-588)1327031213 (DE-627)1886543038 aut Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl 14 November 2023 22 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 23.04.2024 To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Roullet, Jean-Baptiste verfasserin aut Cesaro, Samuele verfasserin aut DiBacco, Melissa L. verfasserin aut Arning, Erland verfasserin aut Rotenberg, Alexander verfasserin aut Lee, Henry H. C. verfasserin aut Opladen, Thomas 1974- verfasserin (DE-588)124489656 (DE-627)642820481 (DE-576)335321291 aut Jeltsch, Kathrin 1981- verfasserin (DE-588)144019353 (DE-627)656815140 (DE-576)340367520 aut García-Cazorla, Àngels verfasserin aut Juliá-Palacios, Natalia verfasserin aut Gibson, K. Michael verfasserin aut Bertoldi, Mariarita verfasserin aut Pearl, Phillip L. 1958- verfasserin (DE-588)1219985287 (DE-627)1736103814 aut Enthalten in Human genetics Berlin : Springer, 1964 142(2023), 12, Seite 1755-1776 Online-Ressource (DE-627)253723973 (DE-600)1459188-1 (DE-576)072373008 1432-1203 nnns volume:142 year:2023 number:12 pages:1755-1776 extent:22 https://doi.org/10.1007/s00439-023-02613-6 Verlag Resolving-System kostenfrei Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2403 GBV_ILN_2403 ISIL_DE-LFER AR 142 2023 12 1755-1776 22 2013 01 DE-16-250 4514899666 00 --%%-- --%%-- --%%-- --%%-- l01 23-04-24 2403 01 DE-LFER 4521200621 00 --%%-- --%%-- n --%%-- l01 07-05-24 2403 01 DE-LFER https://doi.org/10.1007/s00439-023-02613-6 2013 01 DE-16-250 00 s hd2023 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_14 2013 01 DE-16-250 03 s s_22 2013 01 DE-16-250 04 p (DE-627)1484119673 Opladen, Thomas 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_8 2013 01 DE-16-250 05 p (DE-627)1497344778 Jeltsch, Kathrin 2013 01 DE-16-250 05 k (DE-627)1416822720 Extern 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_9 |
| spelling |
10.1007/s00439-023-02613-6 doi (DE-627)1886542252 (DE-599)KXP1886542252 (OCoLC)1443669417 DE-627 ger DE-627 rda eng Tokatly Latzer, Itay verfasserin (DE-588)1327031213 (DE-627)1886543038 aut Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl 14 November 2023 22 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 23.04.2024 To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Roullet, Jean-Baptiste verfasserin aut Cesaro, Samuele verfasserin aut DiBacco, Melissa L. verfasserin aut Arning, Erland verfasserin aut Rotenberg, Alexander verfasserin aut Lee, Henry H. C. verfasserin aut Opladen, Thomas 1974- verfasserin (DE-588)124489656 (DE-627)642820481 (DE-576)335321291 aut Jeltsch, Kathrin 1981- verfasserin (DE-588)144019353 (DE-627)656815140 (DE-576)340367520 aut García-Cazorla, Àngels verfasserin aut Juliá-Palacios, Natalia verfasserin aut Gibson, K. Michael verfasserin aut Bertoldi, Mariarita verfasserin aut Pearl, Phillip L. 1958- verfasserin (DE-588)1219985287 (DE-627)1736103814 aut Enthalten in Human genetics Berlin : Springer, 1964 142(2023), 12, Seite 1755-1776 Online-Ressource (DE-627)253723973 (DE-600)1459188-1 (DE-576)072373008 1432-1203 nnns volume:142 year:2023 number:12 pages:1755-1776 extent:22 https://doi.org/10.1007/s00439-023-02613-6 Verlag Resolving-System kostenfrei Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2403 GBV_ILN_2403 ISIL_DE-LFER AR 142 2023 12 1755-1776 22 2013 01 DE-16-250 4514899666 00 --%%-- --%%-- --%%-- --%%-- l01 23-04-24 2403 01 DE-LFER 4521200621 00 --%%-- --%%-- n --%%-- l01 07-05-24 2403 01 DE-LFER https://doi.org/10.1007/s00439-023-02613-6 2013 01 DE-16-250 00 s hd2023 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_14 2013 01 DE-16-250 03 s s_22 2013 01 DE-16-250 04 p (DE-627)1484119673 Opladen, Thomas 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_8 2013 01 DE-16-250 05 p (DE-627)1497344778 Jeltsch, Kathrin 2013 01 DE-16-250 05 k (DE-627)1416822720 Extern 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_9 |
| allfields_unstemmed |
10.1007/s00439-023-02613-6 doi (DE-627)1886542252 (DE-599)KXP1886542252 (OCoLC)1443669417 DE-627 ger DE-627 rda eng Tokatly Latzer, Itay verfasserin (DE-588)1327031213 (DE-627)1886543038 aut Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl 14 November 2023 22 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 23.04.2024 To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Roullet, Jean-Baptiste verfasserin aut Cesaro, Samuele verfasserin aut DiBacco, Melissa L. verfasserin aut Arning, Erland verfasserin aut Rotenberg, Alexander verfasserin aut Lee, Henry H. C. verfasserin aut Opladen, Thomas 1974- verfasserin (DE-588)124489656 (DE-627)642820481 (DE-576)335321291 aut Jeltsch, Kathrin 1981- verfasserin (DE-588)144019353 (DE-627)656815140 (DE-576)340367520 aut García-Cazorla, Àngels verfasserin aut Juliá-Palacios, Natalia verfasserin aut Gibson, K. Michael verfasserin aut Bertoldi, Mariarita verfasserin aut Pearl, Phillip L. 1958- verfasserin (DE-588)1219985287 (DE-627)1736103814 aut Enthalten in Human genetics Berlin : Springer, 1964 142(2023), 12, Seite 1755-1776 Online-Ressource (DE-627)253723973 (DE-600)1459188-1 (DE-576)072373008 1432-1203 nnns volume:142 year:2023 number:12 pages:1755-1776 extent:22 https://doi.org/10.1007/s00439-023-02613-6 Verlag Resolving-System kostenfrei Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2403 GBV_ILN_2403 ISIL_DE-LFER AR 142 2023 12 1755-1776 22 2013 01 DE-16-250 4514899666 00 --%%-- --%%-- --%%-- --%%-- l01 23-04-24 2403 01 DE-LFER 4521200621 00 --%%-- --%%-- n --%%-- l01 07-05-24 2403 01 DE-LFER https://doi.org/10.1007/s00439-023-02613-6 2013 01 DE-16-250 00 s hd2023 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_14 2013 01 DE-16-250 03 s s_22 2013 01 DE-16-250 04 p (DE-627)1484119673 Opladen, Thomas 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_8 2013 01 DE-16-250 05 p (DE-627)1497344778 Jeltsch, Kathrin 2013 01 DE-16-250 05 k (DE-627)1416822720 Extern 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_9 |
| allfieldsGer |
10.1007/s00439-023-02613-6 doi (DE-627)1886542252 (DE-599)KXP1886542252 (OCoLC)1443669417 DE-627 ger DE-627 rda eng Tokatly Latzer, Itay verfasserin (DE-588)1327031213 (DE-627)1886543038 aut Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl 14 November 2023 22 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 23.04.2024 To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Roullet, Jean-Baptiste verfasserin aut Cesaro, Samuele verfasserin aut DiBacco, Melissa L. verfasserin aut Arning, Erland verfasserin aut Rotenberg, Alexander verfasserin aut Lee, Henry H. C. verfasserin aut Opladen, Thomas 1974- verfasserin (DE-588)124489656 (DE-627)642820481 (DE-576)335321291 aut Jeltsch, Kathrin 1981- verfasserin (DE-588)144019353 (DE-627)656815140 (DE-576)340367520 aut García-Cazorla, Àngels verfasserin aut Juliá-Palacios, Natalia verfasserin aut Gibson, K. 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10.1007/s00439-023-02613-6 doi (DE-627)1886542252 (DE-599)KXP1886542252 (OCoLC)1443669417 DE-627 ger DE-627 rda eng Tokatly Latzer, Itay verfasserin (DE-588)1327031213 (DE-627)1886543038 aut Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl 14 November 2023 22 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 23.04.2024 To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Roullet, Jean-Baptiste verfasserin aut Cesaro, Samuele verfasserin aut DiBacco, Melissa L. verfasserin aut Arning, Erland verfasserin aut Rotenberg, Alexander verfasserin aut Lee, Henry H. C. verfasserin aut Opladen, Thomas 1974- verfasserin (DE-588)124489656 (DE-627)642820481 (DE-576)335321291 aut Jeltsch, Kathrin 1981- verfasserin (DE-588)144019353 (DE-627)656815140 (DE-576)340367520 aut García-Cazorla, Àngels verfasserin aut Juliá-Palacios, Natalia verfasserin aut Gibson, K. Michael verfasserin aut Bertoldi, Mariarita verfasserin aut Pearl, Phillip L. 1958- verfasserin (DE-588)1219985287 (DE-627)1736103814 aut Enthalten in Human genetics Berlin : Springer, 1964 142(2023), 12, Seite 1755-1776 Online-Ressource (DE-627)253723973 (DE-600)1459188-1 (DE-576)072373008 1432-1203 nnns volume:142 year:2023 number:12 pages:1755-1776 extent:22 https://doi.org/10.1007/s00439-023-02613-6 Verlag Resolving-System kostenfrei Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_2403 GBV_ILN_2403 ISIL_DE-LFER AR 142 2023 12 1755-1776 22 2013 01 DE-16-250 4514899666 00 --%%-- --%%-- --%%-- --%%-- l01 23-04-24 2403 01 DE-LFER 4521200621 00 --%%-- --%%-- n --%%-- l01 07-05-24 2403 01 DE-LFER https://doi.org/10.1007/s00439-023-02613-6 2013 01 DE-16-250 00 s hd2023 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_14 2013 01 DE-16-250 03 s s_22 2013 01 DE-16-250 04 p (DE-627)1484119673 Opladen, Thomas 2013 01 DE-16-250 04 k (DE-627)1416740988 Zentrum für Kinder- und Jugendmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_8 2013 01 DE-16-250 05 p (DE-627)1497344778 Jeltsch, Kathrin 2013 01 DE-16-250 05 k (DE-627)1416822720 Extern 2013 01 DE-16-250 05 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 05 s pos_9 |
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Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants Itay Tokatly Latzer, Jean-Baptiste Roullet, Samuele Cesaro, Melissa L. DiBacco, Erland Arning, Alexander Rotenberg, Henry H. C. Lee, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K. Michael Gibson, Mariarita Bertoldi, Phillip L. Pearl |
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phenotypic correlates of structural and functional protein impairments resultant from aldh5a1 variants |
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Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants |
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To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Gesehen am 23.04.2024 |
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To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Gesehen am 23.04.2024 |
| abstract_unstemmed |
To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders. Gesehen am 23.04.2024 |
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