SLC6A19, which encodes the amino acid transporter B0AT1, was first reported in relation to autosomal recessive Hartnup disease in 2004 (Kleta et al, PMID: 15286787 AND Seow et al, PMID: 15286788). At least 19 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The first proband with this disorder was reported by Baron et al in 1956 (PMID: 13358233). This case report established neutral hyperaminoaciduria as the primary phenotype observed, with others such as skin rash, developmental delay, difficulty walking, and muscle atrophy also arising in some with null B0AT1 transport activity. Since that publication and genetic characterization in Kleta et al, variants in this gene have been reported in at least 19 more probands mostly of European or Asian ancestry (PMIDs: 15286787, 15286788, 18484095). Variants in this gene segregated with disease in about 10 additional family members, yielding a total combined LOD score of 6. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, with defective amino acid transport causing the characteristic neutral hyperaminoaciduria and limiting the absorption within the kidney and/or small intestine. Of note, this gene has also been potentially implicated in iminoglycinuria and hyperglycinuria in combination with other transporters such as SLC36A2 and SLC6A20. These assertions will be assessed separately. This gene-disease association is also supported by biochemical function data, RNA and protein expression, and a knockout mouse model. SLC6A19's neutral amino acid transport function combined with the near-exclusive expression in the kidney and small intestine provides significant evidence towards the pathogenicity. The knockout mouse model also showed the characteristic neutral hyperaminoaciduria and defective transport, as well as short stature. In summary, SLC6A19 is definitively associated with autosomal recessive Hartnup disease.This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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