Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity

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, Yan Huang, Hugo Vega, James P. Snyder, Gretchen A. Golas, Cynthia J. TifftCornelius F. Boerkoel, Richard W. Hanson, Stephen F. Traynelis, Douglas S. Kerr, William A. Gahl

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)161-170
Number of pages10
JournalMolecular Genetics and Metabolism
Volume113
Issue number3
DOIs
StatePublished - Nov 1 2014

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Keywords

  • Developmental delay
  • Dysmorphism
  • Hypoglycemia
  • Lactic acidemia
  • Multiple genetic disorders
  • Protein structure-function

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Adams, D. R., Yuan, H., Holyoak, T., Arajs, K. H., Hakimi, P., Markello, T. C., Wolfe, L. A., Vilboux, T., Burton, B. K., Fajardo, K. F., Grahame, G., Holloman, C., Sincan, M., Smith, A. C. M., Wells, G. A., Huang, Y., Vega, H., Snyder, J. P., Golas, G. A., ... Gahl, W. A. (2014). Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. Molecular Genetics and Metabolism, 113(3), 161-170. https://doi.org/10.1016/j.ymgme.2014.04.001