Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith–Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity
| Autor: | Stephen F. Traynelis, Karin Fuentes Fajardo, Lynne A. Wolfe, Conisha Holloman, Barbara K. Burton, Richard W. Hanson, James P. Snyder, Cornelius F. Boerkoel, Todd Holyoak, Ann C.M. Smith, David R. Adams, Hongjie Yuan, Cynthia J. Tifft, Thierry Vilboux, Gretchen Golas, Yan Huang, Douglas S. Kerr, Murat Sincan, Katrina H. Arajs, Parvin Hakimi, George Grahame, Hugo Vega, William A. Gahl, Thomas C. Markello, Gordon Wells |
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| Rok vydání: | 2014 |
| Předmět: |
Retinoic acid induced 1
Endocrinology Diabetes and Metabolism DNA Mutational Analysis Molecular Sequence Data Nonsense mutation Mutation Missense Single-nucleotide polymorphism Protein structure function Polymorphism Single Nucleotide Receptors N-Methyl-D-Aspartate Biochemistry Article Endocrinology Genetics medicine Humans Amino Acid Sequence Child Molecular Biology Genetic Association Studies Exome sequencing Base Sequence biology Intracellular Signaling Peptides and Proteins Smith–Magenis syndrome medicine.disease 3. Good health HEK293 Cells Child Preschool Mutation (genetic algorithm) Trans-Activators biology.protein Female Phosphoenolpyruvate Carboxykinase (GTP) GRIN2B Smith-Magenis Syndrome Phosphoenolpyruvate Carboxykinase (ATP) Transcription Factors |
| Zdroj: | Molecular Genetics and Metabolism. 113:161-170 |
| ISSN: | 1096-7192 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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