Day 2 :
National Institutes of Health Bethesda, USA
Keynote: Altered UBIAD1 prenyltransferase function in schnyder cornea dystrophy affects cholesterol metabolism and mitochondrial function
Time : 09:30-10:15
Michael L Nickerson has obtained his PhD in Molecular Medicine from the George Washington University. He has made significant contributions to disease gene identification using positional cloning, including an altered Birt-Hogg-Dubé gene in chromophobe RCC, fumarate hydratase in papillary RCC, the dead-end gene in testicular cancer, and the UBIAD1 gene in Schnyder Corneal Dystrophy. More recently, he has sequenced urologic tumor genomes and identified alterations in TET2 in prostate cancer and the BRCA pathway in bladder and kidney cancer, which have been translated to a clinical trial starting in 2016. He is an active participant in Precision Medicine, ClinVar and the TCGA project.
Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. Germline UBIAD1 variants introduce missense mutations in over 50 SCD families, including four large families from Finland who share a likely founder mutation. UBIAD1 was recently shown to catalyze synthesis of two mitochondrial electron carriers, menaquinone-4 (MK-4) and coenzyme Q10/ubiquinone (CoQ10). MK-4 is the predominant active form of vitamin K and an important cofactor in bone metabolism and blood clotting. We show SCD-altered UBIAD1 results in reduced MK-4 synthesis and molecular models indicate mutations disrupt active site residues and transmembrane helices. Yeast two-hybrid screening, co-immunoprecipitation, and confocal microscopy show a physical interaction between UBIAD1 and the cholesterol synthesis and storage enzymes HMGCR and SOAT1. Molecular models indicate cholesterol and geranylgeranyl diphosphate, a substrate for MK-4 synthesis, binding the same substrate binding cleft and likely compete for occupancy of UBIAD1. Vitamin K was originally identified by depletion of dietary cholesterol in chickens, which co-depleted vitamin K resulting in hemorrhages and uncontrolled bleeding. Our data suggests a first physiologic role for endogenously produced vitamin K in maintaining cornea health and visual acuity, in addition to its role in blood clotting. The data indicates that the synthesis of vitamin K, CoQ10 and cholesterol may be tightly linked with implications for vision, mitochondria function, cardiovascular health and cancer.
- Nickerson M L, Bosley A, Weiss J S, Kostiha B N, Hirota Y, Brandt W, Esposito D, Kinoshita S, Wessjohann L, Morham S G, Andresson T, Kruth H S, Okano T, and Dean M (2013) The UBIAD1 prenyltransferase links menaquinone-4 synthesis to cholesterol metabolic enzymes. Hum Mutat 34: 317-329.
- Fredericks, W J, Mc Garvey, T Wang, H Zheng Y, Fredericks N J, Yin H, Wang, L P, Hsiao W, Lee R, Weiss J S, Nickerson, M L Kruth, H S Rauscher F J and Malkowicz S B (2013) The TERE1 protein interacts with mitochondrial TBL2: regulation of transmembrane potential, ROS/RNS and SXR target genes. J Cell Biochem 114 (9): 2170-87.
- Fredericks W J, Mc Garvey T, Wang H, Lal P, Puthiyaveettil R, Tomaszewski J, Sepulveda J, Labelle E, Weiss J S, Kruth H S, Brandt W, Wessjohann L A and Malkowicz S B (2011) The bladder tumor suppressor protein TERE1 (UBIAD1) modulates cell cholesterol: Implications for tumor progression. DNA Cell Biol 11: 851-64.
- Nickerson M L, Kostiha B N, Brandt W, Fredericks W, Xu K P, Yu F S, Gold B, Chodosh J, Goldberg M, Lu D W, Yamada M, Tervo T M, Grutzmacher D, Croasdale C, Hoeltzenbein M, Sutphin J, Malkowicz S B, Wessjohann L, Kruth H S, Dean M and Weiss J S (2010) UBIAD1 mutations alter a mitochondrial prenyltransferase to cause Schnyder Corneal Dystrophy. PLoS ONE 5 (5): e10760.
- Weiss J S, Kruth H S, Kuivaniemi H, Tromp G, White P S, Winters R S, Lisch W, Henn W, Denninger E, Krause M, Wasson P, Ebenezer N, Mahurkar S and Nickerson M L (2007) Mutations in the UBIAD1 gene on chromosome 1p36 cause schnyder crystalline corneal dystrophy. Invest Ophthalmol Vis Sci 48: 5007-5012.
Columbia University, USA
Keynote: Use of Carrier exome screening for prevention of childhood malignancies and other sever congenital abnormalities
Time : 10:15-11:00
Peter L Nagy is Board Certified in Anatomic and Molecular Genetic Pathology. He was a Principal Investigator on multiple NIH funded studies at University of Iowa and Columbia University and served as an Associate Director of Personalized Genomic Medicine Laboratory at Columbia University Medical Center. He has established an array of clinical next-generation sequencing tests including whole exome and transcriptome testing for constitutional and somatic (cancer) disorders. At Medical Neurogenetics Laboratories, he is continuing his groundbreaking work on developing computational tools to improve the clinical specificity and sensitivity of next generation sequencing data analysis.
Our work with the Columbia University Medical Center Precision Medicine for Kids with cancer (PIP-seq) project has shown that a significant percentage of pediatric malignancies arise because of genetic predisposition. We can consider cancer predisposition as a specialized case of the parents being carriers for a specific genetic disorder. MNG laboratories has developed a whole exome carrier test designed to fulfill the preconception genetic counseling needs of couples who suspect, based on shared ethnicity or family history, that they are potentially at risk of having children with debilitating health problems, including development of pediatric malignancies. In my presentation, I will discuss the technical, practical and ethical considerations to make such testing widely available for risk couples.