TY - JOUR
T1 - Type 1 hyperlipoproteinemia due to compound heterozygous rare variants in GCKR
AU - Shetty, Shilpa
AU - Xing, Chao
AU - Garg, Abhimanyu
N1 - Funding Information:
This work was supported by the Southwest Medical Foundation and National Institutes of Health Grant UL1TR001105. Author Contributions: S.S. conceptualized the study, and drafted the initial manuscript. C.X. carried out whole-exome sequencing and data analysis and reviewed and revised the manuscript. A.G. conceptualized the study, evaluated the patient, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Publisher Copyright:
Copyright © 2016 by the Endocrine Society.
PY - 2016/11
Y1 - 2016/11
N2 - 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. Case Description: 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,andfish oiltherapy.SangersequencingoftheknownT1HLPgenesin thispatientdidnotreveal any disease-causing mutations.Whole-exomesequencing revealedcompoundheterozygous 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. (J Clin Endocrinol Metab 101: 3884-3887, 2016).
AB - 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. Case Description: 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,andfish oiltherapy.SangersequencingoftheknownT1HLPgenesin thispatientdidnotreveal any disease-causing mutations.Whole-exomesequencing revealedcompoundheterozygous 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. (J Clin Endocrinol Metab 101: 3884-3887, 2016).
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U2 - 10.1210/jc.2016-2179
DO - 10.1210/jc.2016-2179
M3 - Article
C2 - 27403930
AN - SCOPUS:84994868564
VL - 101
SP - 3884
EP - 3887
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 11
ER -