Janice J. Chou, Ph.D.
Section on Cellular Differentiation
Molecular Genetics of Heritable Human Disorders
We conduct research to delineate the pathophysiology and develop novel therapies for the three subtypes of type I glycogen storage disease (GSD-I), GSD-Ia, GSD-Ib, and GSD-Irs (GSD-I related syndrome). GSD-Ia is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), GSD-Ib is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT or SLC37A4), and GSD-Irs, also known as severe congenital neutropenia syndrome type 4. is caused by a deficiency in G6Pase-β. G6Pase-α and G6Pase-β are endoplasmic reticulum (ER)-bound G6P hydrolases, with active sites lying inside the lumen, which depend upon G6PT to translocate G6P from the cytoplasm into the ER lumen. The G6PT/G6Pase-α complex maintains interprandial glucose homeostasis while the G6PT/G6Pase-β complex maintains energy homeostasis and functionality of neutrophils. GSD-Ia and GSD-Ib patients manifest a common metabolic phenotype of impaired glucose homeostasis not shared by GSD-Irs. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and myeloid dysfunction not shared by GSD-Ia. Inactivation of G6PT or G6Pase-β in neutrophils leads to enhanced apoptosis that underlies neutropenia in GSD-Ib and GSD-Irs. A deficiency in either G6PT or G6Pase-β in neutrophils prevents recycling of glucose from the ER to the cytoplasm, leading to impaired energy homeostasis that underlies neutrophil dysfunction in GSD-Ib and GSD-Irs. There is no cure for GSD-Ia, GSD-Ib, and GSD-Irs. We have developed animal models of GSD-Ia, GSD-Ib and GSD-Irs which are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy. Also, we have generated several efficacious G6Pase-α-expressing and G6PT-expressing recombinant adeno-associated virus (rAAV) vectors and provided a proof of principle gene therapy in murine GSD-Ia and GSD-Ib that is safe, efficacious, and appropriate for entering clinical trials. In 2018, a rAAV vector expressing human G6Pase-α developed in this laboratory (US patent number: 9,644,216; European patent number: EP3074510) was selected for the phase I/II clinical trial for human GSD-Ia (ClinicalTrials.gov Identifier: NCT03517085).
Dr. Janice Y. Chou is the Section Chief on Cellular Differentiation, NICHD, a position she has held since 1983. In this role, Dr. Chou conducts research to understand the molecular genetics and pathogenesis of glycogen storage diseases type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC); GSD-Ib, deficient in the G6P transporter (G6PT or SLC37A4); and GSD-Irs, deficient in G6Pase-β (or G6PC3). GSD-Irs is also known as severe congenital neutropenia syndrome type 4. Through the use of transgenic mouse models, Dr Chou also pioneers preclinical development of gene-based therapies for these disorders. Her rAAV-mediated gene therapies in murine GSD-Ia and GSD-Ib have provided proof of principle studies that establish gene therapy for GSD-Ia and GSD-Ib to be safe, efficacious, and appropriate for entering clinical trials. One human G6Pase-α-expressing rAAV vector developed in this laboratory (US patent number: 9,644,216; European patent number: EP3074510) was selected for the 2018 phase I/II clinical trial for human GSD-Ia (ClinicalTrials.gov Identifier: NCT03517085). Dr. Chou received her Ph.D. degree in Biochemistry from the University of Utah and began her postgraduate scientific career at NIDDK, NIH. She then joined NICHD and was promoted to Section Chief in 1983. During her career at the NIH, Dr. Chou has made contributions across a wide area of gene regulation and cellular differentiation, including the development of some of the first temperature-sensitive cell lines, the elucidation of the mechanism of cell transformation, and the characterization of gene regulatory sequences and transcription factors in the context of developmentally regulated genes. Since 1993, her research has focused on the molecular genetics of human heritable disorders. She has established the genetic basis of methionine adenosyltransferase deficiency, GSD-Ia, GSD-Ib, and GSD-Irs, and developed gene therapy for GSD-Ia and GSD-Ib. Dr. Chou holds four patents and has served as a member of the Personnel Promotion Committee at NICHD, the Selection Committee of the Reproduction Scientist Development Program, and the Association for Glycogen Storage Diseases. She has received a Superior Service Award from the US Public Health Service and a Scientific Achievement Award from the Chinese Medical and Health Association. She was also cited in the Maryland Women's History Resource Kit. In recent years Dr. Chou delivered the Plenary Lecture of the International symposium on hepatic GSDs in Lyon, France, 2012, The EMG Lecture of the 45th European Metabolic Group Meeting in Groningen, The Netherlands, 2013, and Gene Therapy in GSD, International GSD Conference, Groningen, The Netherland, 2017. Dr. Chou has authored over 200 peer-reviewed scientific papers, review articles, and book chapters.
Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat Rev Endocrinol. 2010;6(12):676-88.
Jun HS, Weinstein DA, Lee YM, Mansfield BC, Chou JY. Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib. Blood. 2014;123(18):2843-53.
Zhang L, Cho JH, Arnaoutova I, Mansfield BC, Chou JY. An evolutionary approach to optimizing glucose-6-phosphatase-α enzymatic activity for gene therapy of glycogen storage disease type Ia. J Inherit Metab Dis. 2019;42(3):470-479.
Lee YM, Jun HS, Pan CJ, Lin SR, Wilson LH, Mansfield BC, Chou JY. Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy. Hepatology. 2012;56(5):1719-29.
Cho JH, Kim GY, Pan CJ, Anduaga J, Choi EJ, Mansfield BC, Chou JY. Downregulation of SIRT1 signaling underlies hepatic autophagy impairment in glycogen storage disease type Ia. PLoS Genet. 2017;13(5):e1006819.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Genetics and Genomics
This page was last updated on August 19th, 2020