Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1998216 | Molecular Genetics and Metabolism | 2014 | 43 Pages |
Abstract
The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
Keywords
PCK1BSPNMDAN-methyl d-aspartateμMECHOCGHEC50nAMDOAAGAPDHPDBRMSDKClPEPCK-MDMEMGTPHEPESNaClPEPCK-CIPTGDTTRAI14-(2-hydroxyethyl)-1-piperazineethanesulfonic acidDulbecco's modified Eagle Mediumguanosine-5′-triphosphateKcatoxaloacetic acidLactic acidemiaElectroencephalogrampolyacrylamide gel electrophoresis in sodium dodecyl sulfateechocardiogramisopropyl β-D-1-thiogalactopyranosidedevelopmental delaycomparative genomic hybridizationdithiothreitolDysmorphismroot-mean-square-deviationProtein structure-functionSodium chlorideSmith–Magenis syndromephosphoenolpyruvate carboxykinase 1millimolarmicromolarEEGwild typehalf maximal effective concentrationhypoglycemiaProtein Data BankSingle nucleotide polymorphismSMSSNPoptical densityCootPotassium chlorideglyceraldehyde-3-phosphate dehydrogenase
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Authors
David R. Adams, Hongjie Yuan, Todd Holyoak, Katrina H. Arajs, Parvin Hakimi, Thomas C. Markello, Lynne A. Wolfe, Thierry Vilboux, Barbara K. Burton, Karin Fuentes Fajardo, George Grahame, Conisha Holloman, Murat Sincan, Ann C.M. Smith, Gordon A. Wells,