Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles

@article{Mayfield2012SurrogateGA,
  title={Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles},
  author={Jacob A. Mayfield and Meara W Davies and Dago Dimster-Denk and Nick Pleskac and Sean McCarthy and Elizabeth A. Boydston and Logan Fink and Xinlei Lin and Ankur S Narain and Michael Meighan and Jasper Rine},
  journal={Genetics},
  year={2012},
  volume={190},
  pages={1309 - 1323}
}
Cystathionine-β-synthase (CBS) deficiency is a human genetic disease causing homocystinuria, thrombosis, mental retardation, and a suite of other devastating manifestations. Early detection coupled with dietary modification greatly reduces pathology, but the response to treatment differs with the allele of CBS. A better understanding of the relationship between allelic variants and protein function will improve both diagnosis and treatment. To this end, we tested the function of 84 CBS alleles… 
A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
TLDR
A ‘proactive’ comprehensive missense variant effect map for human CBS was described, which identified disease variants and predicted both disease severity and human clinical response to vitamin B6, even for rare variants not previously seen in the clinic.
A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
TLDR
It is demonstrated that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
Mono and Dual Cofactor Dependence of Human Cystathionine β-Synthase Enzyme Variants In Vivo and In Vitro
TLDR
It is hypothesized that some variants of the CBS protein caused a modest, yet significant, destabilization of the native state of the protein, and that the functional impact of the amino acid substitutions caused by these alleles can be influenced by cofactor(s) even when the affected amino acid is distant from the cofactor binding site.
Correction of Cystathionine β‐Synthase Deficiency in Mice by Treatment with Proteasome Inhibitors
TLDR
The data show that treatment with proteostasis modulators can restore significant enzymatic activity to mutant misfolded CBS enzymes and suggests that they may be useful in treating certain types of genetic diseases caused by missense mutations.
Assessing computational predictions of the phenotypic effect of cystathionine‐beta‐synthase variants
TLDR
A computational challenge under the CAGI framework is created to evaluate how well different methods can predict the phenotypic effect(s) of CBS single amino acid substitutions using a blinded experimental data set.
A yeast‐based complementation assay elucidates the functional impact of 200 missense variants in human PSAT1
TLDR
A functional assay that leverages the evolutionary conservation of an enzyme in the serine biosynthesis pathway, phosphoserine aminotransferase, and the ability of the human protein‐coding sequence (PSAT1) to functionally replace its yeast ortholog (SER1) is described.
Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate
TLDR
It is proposed that a distinct group of heme-responsive CBS mutations may exist and that the heme pocket of CBS may become an important target for designing novel therapies for homocystinuria.
Polymorphisms of cystathionine beta-synthase gene are associated with susceptibility to sepsis
TLDR
There is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility.
Cofactors and metabolites as protein folding helpers in metabolic diseases.
TLDR
The role of riboflavin supplementation in the treatment of fatty acid β-oxidation disorders will be thoroughly analyzed, focusing on recent reports that shed light on the molecular basis of vitamin responsiveness.
INFERRING THE FUNCTIONAL SIGNIFICANCE OF MISSENSE MUTATIONS INVOLVED IN MENDELIAN PHENOTYPES
Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical
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TLDR
It is reported here that a mutation which deletes the carboxy-terminal 145 amino acids of CBS can functionally suppress the phenotype of several CBS mutant alleles found in homocystinurics when expressed in yeast, suggesting a new drug target to treat homocysteine-related vascular disease.
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TLDR
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TLDR
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TLDR
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TLDR
Screening for mutations by expressing patient cDNA segments in E. coli permitted us to separate the parental CBS alleles, localize each mutation within one third of the cDNA, and functionally analyse the mutant protein.
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TLDR
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TLDR
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