Phenotypic prediction in glutaric aciduria type 1 combining in silico and in vitro modeling with real-world data.
J Inherit Metab Dis
; 46(3): 391-405, 2023 05.
Article
en En
| MEDLINE
| ID: mdl-37078465
ABSTRACT
Glutaric aciduria type 1 (GA1) is caused by inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). To further understand the unclear genotype-phenotype correlation, we transfected mutated GCDH into COS-7 cells resembling known biallelic GCDH variants of 47 individuals with GA1. In total, we modeled 36 genotypes with 32 missense variants. Spectrophotometry demonstrated an inverse correlation between residual enzyme activity and the urinary concentration of glutaric acid and 3-hydroxyglutaric acid, confirming previous studies (Pearson correlation, r = -0.34 and r = -0.49, p = 0.045 and p = 0.002, respectively). In silico modeling predicted high pathogenicity for all genotypes, which caused a low enzyme activity. Western blotting revealed a 2.6-times higher GCDH protein amount in patients with an acute encephalopathic crisis (t-test, p = 0.015), and high protein expression correlated with high in silico protein stability (Pearson correlation, r = -0.42, p = 0.011). The protein amount was not correlated with the enzyme activity (Pearson correlation, r = 0.09, p = 0.59). To further assess protein stability, proteolysis was performed, showing that the p.Arg88Cys variant stabilized a heterozygous less stable variant. We conclude that an integration of different data sources helps to predict the complex clinical phenotype in individuals with GA1.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Encefalopatías Metabólicas
/
Errores Innatos del Metabolismo de los Aminoácidos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
J Inherit Metab Dis
Año:
2023
Tipo del documento:
Article
País de afiliación:
Alemania