Tyrosine hydroxylase variants influence protein expression, cellular localization, stability, enzymatic activity and the physical interaction between tyrosine hydroxylase and GTP cyclohydrolase 1.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis catalyzing the tetrahydrobiopterin (BH)-dependent hydroxylation of tyrosine to L-DOPA. Here, we analyzed 25 TH variants associated with various degrees of dopa-responsive dystonia and evaluate the effect of each variant on protein stability, activity and cellular localization. Furthermore, we investigated the physical interaction between TH and human wildtype (wt) GTP cyclohydrolase 1 (GTPCH) and the effect of variants on this interaction.

Modeling dose-response functions for combination treatments with log-logistic or Weibull functions.

Dose-response curves of new substances in toxicology and related areas are commonly fitted using log-logistic functions. In more advanced studies, an additional interest is often how these substances will behave when applied in combination with a second substance. Here, an essential question for both design and analysis of these combination experiments is whether the resulting dose-response function will still be a member of the class of log-logistic functions, and, if so, what function parameters will result for the combined substances.

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.

Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients.