title: Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes.
abstract: Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene- and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease.
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rees
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.forename: Sarah
authors.initials: S
authors.lastname: Ruppert
authors.forename: Clesson
authors.initials: C
authors.lastname: Turner
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Beer
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Swift
authors.forename: Mario A
authors.initials: MA
authors.lastname: Morken
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.forename: Ilana
authors.initials: I
authors.lastname: Blech
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000368:Aged; D019943:Amino Acid Substitution; D018389:Codon, Nonsense; D015331:Cohort Studies; D019143:Evolution, Molecular; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D014644:Genetic Variation; D005941:Glucokinase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C485100:GCKR protein, human; D011994:Recombinant Proteins; D014280:Triglycerides; D005941:Glucokinase