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

Majid Alfadhel, Marwan Nashabat, Hanan Al Qahtani, Ahmed Alfares, Fuad Al Mutairi, Hesham Al Shaalan, Ganka V. Douglas, Klaas Wierenga, Jane Juusola, Muhammad Talal Alrifai, Stefan T. Arold, Fowzan Alkuraya, Qais Abu Ali

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22 Scopus citations


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.
Original languageEnglish (US)
Pages (from-to)1263-1268
Number of pages6
Issue number11
StatePublished - 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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