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Phenotypic Correlates of Structural and Functional Protein Impairments Resultant from ALDH5A1 Variants.
Latzer, Itay Tokatly; Roullet, Jean-Baptiste; Cesaro, Samuele; DiBacco, Melissa L; Arning, Erland; Rotenberg, Alexander; Lee, Henry H C; Opladen, Thomas; Jeltsch, Kathrin; García-Cazorla, Àngels; Juliá-Palacios, Natalia; Gibson, K Michael; Bertoldi, Mariarita; Pearl, Phillip L.
Afiliação
  • Latzer IT; Boston Children's Hospital, Harvard Medical School.
  • Roullet JB; Washington State University.
  • Cesaro S; University of Verona.
  • DiBacco ML; Boston Children's Hospital, Harvard Medical School.
  • Arning E; Baylor Scott & White Research Institute.
  • Rotenberg A; Boston Children's Hospital, Harvard Medical School.
  • Lee HHC; Boston Children's Hospital, Harvard Medical School.
  • Opladen T; University Children's Hospital Heidelberg.
  • Jeltsch K; University Children's Hospital Heidelberg.
  • García-Cazorla À; Institut de Recerca, Hospital Sant Joan de Déu.
  • Juliá-Palacios N; Institut de Recerca, Hospital Sant Joan de Déu.
  • Gibson KM; Washington State University.
  • Bertoldi M; University of Verona.
  • Pearl PL; Boston Children's Hospital, Harvard Medical School.
Res Sq ; 2023 Jul 10.
Article em En | MEDLINE | ID: mdl-37503297
Objective: To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Methods: 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. Results: 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). Conclusions: 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Res Sq Ano de publicação: 2023 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Res Sq Ano de publicação: 2023 Tipo de documento: Article País de publicação: Estados Unidos