title: Type 1 Hyperlipoproteinemia Due to Compound Heterozygous Rare Variants in GCKR.
abstract: BACKGROUND
  Type 1 hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme elevations in serum triglyceride (TG) levels. Despite considerable progress in identifying several causal genes for T1HLP, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1, the molecular basis of some extremely rare patients presenting with T1HLP remains obscure.
  
  
  METHODS
  We report a 58-year-old Hispanic female who initially presented with serum TG of 4740 mg/dL at age 23 years when she was 3 weeks postpartum and was taking an oral contraceptive for 2 weeks. Over a period of 35 years, she has had recurrent episodes of extreme hypertriglyceridemia (fasting serum TG exceeding 2000 mg/dL), which responded to a reduction of dietary fat, fibrates, and fish oil therapy. Sanger sequencing of the known T1HLP genes in this patient did not reveal any disease-causing mutations. Whole-exome sequencing revealed compound heterozygous rare variants (p.Val103Met and p.Arg540Gln) in the glucokinase regulator (GCKR) gene.
  
  
  CONCLUSIONS
  GCKR encodes glucokinase regulatory protein, which is an inhibitor of glucokinase, an enzyme that drives glucose uptake in the liver. Loss of function GCKR variants, by enhancing glucose uptake in hepatocytes, may induce de novo lipogenesis and TG biosynthesis, resulting in extreme hypertriglyceridemia. We conclude that compound heterozygous rare variants in GCKR cause an extremely rare unique T1HLP, most likely by inducing excessive hepatic lipogenesis.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine (S.S.); McDermott Center for Human Growth and Development and Department of Clinical Sciences (C.X.); and Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition (A.G.), UT Southwestern Medical Center, Dallas, Texas 75390-8537.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Shetty
authors.affiliation: Division of Endocrinology, Department of Internal Medicine (S.S.); McDermott Center for Human Growth and Development and Department of Clinical Sciences (C.X.); and Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition (A.G.), UT Southwestern Medical Center, Dallas, Texas 75390-8537.
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Division of Endocrinology, Department of Internal Medicine (S.S.); McDermott Center for Human Growth and Development and Department of Clinical Sciences (C.X.); and Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition (A.G.), UT Southwestern Medical Center, Dallas, Texas 75390-8537.
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D019943:Amino Acid Substitution; D005260:Female; D006579:Heterozygote; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human