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.

Fig. 1

a Family pedigree, b esotropia and microcephaly, broad forehead, esotropia, low set ears, retrognathia, deep prominent philtrum and sparse eyebrows, c selected MR image of the brain at the level of basal ganglia, coronal T2-WI shows bilateral subinsular white matter hyper intensity (arrows) and right head of caudate atrophy with a tiny cyst (star), d axial T2-WI shows bilateral scattered subcortical and periventricular white matter hyperintensities (arrows)

Fig. 2

3D homology model of human SLC6A9, based on the dopamine transporter (PDB 4xpa). The dopamine analogue 3,4-dichlorophenethylamine (yellow), sodium (magenta), and chloride (cyan) ions have been taken over from the dopamine receptor structure that served as template. The bound ions are expected to be located in the wild-type (but not the S406 mutant) SLC6A9, as they are in the dopamine transporter, because of strict conservation of the ion-binding site. However, the dopamine analogue is of course replaced by glycine in SLC6A9, and the dopamine analogue is only displayed to illustrate the location of S406 with respect to the ligand molecule