Dual role of dysfunctional Asc-1 transporter in distinct human pathologies - human startle disease and developmental delay.

Human startle disease is associated with mutations in distinct genes encoding glycine receptors, transporters or interacting proteins at glycinergic synapses in spinal cord and brainstem. However, a significant number of diagnosed patients does not carry a mutation in the common genes GLRA1 , GLRB , and SLC6A5 Recently, studies on SLC7A10 (Asc-1 alanine-serine-cysteine transporter) knockout mice displaying a startle disease-like phenotype hypothesized that this transporter might represent a novel candidate for human startle disease. Here, we screened 51 patients from our patient cohort negative for the common genes and found three exonic (one missense, two synonymous), seven intronic, and single nucleotide changes in the 5' and 3' untranslated regions. The identified missense mutation Asc-1 G307R from a patient with startle disease and developmental delay was investigated in functional studies. At the molecular level, the mutation Asc-1 G307R did not interfere with cell-surface expression, but disrupted glycine uptake. Substitution of glycine at position 307 to other amino acids e.g. to alanine or tryptophan did not affect trafficking or glycine transport. By contrast, G307K disrupted glycine transport similar to the G307R mutation found in the patient. Structurally, the disrupted function in variants carrying positively charged residues can be explained by local structural rearrangements due to the large positively charged side chain. Thus, our data suggest that SLC7A10 may represent a rare but novel gene associated with human startle disease and developmental delay. Statement of Significance Patients diagnosed with startle disease/hyperekplexia do not always carry mutations in the known associated disease genes ( GLRA1, GLRB, SLC6A5 ). Recently, murine studies suggested SLC7A10 as candidate gene for human startle disease. Within our patient cohort, we found one missense mutation, three exonic silent mutations but also intronic single nucleotide variations as well as variations in the 5' and 3' untranslated regions in SLC7A10 We further concentrated on the structural and functional alterations due to identified missense mutations in Asc-1. The exchange of Gly307 with positively charged residues leads to structural rearrangements accompanied by loss of function. Our data provide evidence that in humans SLC7A10 is a rare gene associated with human startle disease.