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

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.

Citation
Alfadhel, M., Nashabat, M., Qahtani, H. A., Alfares, A., Mutairi, F. A., Shaalan, H. A., … Ali, Q. A. (2016). Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Human Genetics, 135(11), 1263–1268. doi:10.1007/s00439-016-1719-x

Acknowledgements
We wish to thank the family of the patient for their enthusiastic participation. The research by STA reported in this publication was supported by funding from the King Abdullah University of Science and Technology (KAUST).

Publisher
Springer Science and Business Media LLC

Journal
HUMAN GENETICS

DOI
10.1007/s00439-016-1719-x

PubMed ID
27481395

PubMed Central ID
PMC5052303

Additional Links
http://link.springer.com/10.1007/s00439-016-1719-x

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