2. Academic Validation
  3. Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans

Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans

  • Hum Genet. 2016 Nov;135(11):1263-1268. doi: 10.1007/s00439-016-1719-x.
Majid Alfadhel 1,  Marwan Nashabat 2,  Hanan Al Qahtani 3,  Ahmed Alfares 4,  Fuad Al Mutairi 2,  Hesham Al Shaalan 3,  Ganka V Douglas 5,  Klaas Wierenga 6,  Jane Juusola 5,  Muhammad Talal Alrifai 7,  Stefan T Arold 8,  Fowzan Alkuraya 9 10,  Qais Abu Ali 5
Affiliations

Affiliations

  • 1 Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Saudi Arabia. [email protected].
  • 2 Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Saudi Arabia.
  • 3 Medical Imaging Department, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 4 Department of Pediatrics, College of Medicine, Qassim University, Almulyda, Saudi Arabia.
  • 5 GeneDx, Gaithersburg, MD, 20877, USA.
  • 6 Department of Pediatrics, Section of Genetics, The University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
  • 7 Neurology Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (NGHA), King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 8 Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
  • 9 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 10 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
PMID: 27481395 DOI: 10.1007/s00439-016-1719-x
Abstract

Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans.

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