Hartnup disorder, an autosomal recessive defect named after an English family described in 1956 (ref. 1), results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis 1,2 . Using homozygosity mapping in the original family in whom Hartnup disorder was discovered, we confirmed that the critical region for one causative gene was located on chromosome 5p15 (ref. 3). This region is homologous to the area of mouse chromosome 13 that encodes the sodium-dependent amino acid transporter B 0 AT1 (ref. 4). We isolated the human homolog of B 0 AT1, called SLC6A19, and determined its size and molecular organization. We then identified mutations in SLC6A19 in members of the original family in whom Hartnup disorder was discovered and of three Japanese families. The protein product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine and renal proximal tubule and functions as a neutral amino acid transporter.Despite molecular characterization of other proximal tubule transporters, the neutral amino acid carrier defective in Hartnup disorder (OMIM 2345000) has resisted genetic identification 2 . We carried out homozygosity mapping and fine mapping in ten members of two consanguineous families (the siblings in whom Hartnup disorder was originally discovered 1 ; family A; Fig. 1a) and in siblings from the US 5 (family B; Fig. 1a). We found linkage of Hartnup disorder to 5p15 only in family A, with a maximum combined multipoint lod score of 2.31 at 11.24 cM (P ¼ 0.01). This confirmed our previous results showing linkage to chromosome 5p15 (ref.3). In family B, we obtained a maximum multipoint lod score of À2.40 at 15.81 cM.We simultaneously pursued two mouse monoamine transporterrelated orphan genes, Slc6a18 (also called Xtrp2; ref. 6) and Slc6a19 (encoding B 0 AT1; ref. 4). These members of the SLC6 family of transporters map to the mouse chromosomal region that is homologous to human chromosome 5p15. Both Slc6a18 and Slc6a19 showed abundant expression in mouse kidney, as assessed by real time RT-PCR (Fig. 2a). Immunohistochemistry confirmed expression of mouse B 0 AT1 at the brush border of small intestine (data not shown) and kidney proximal tubule cells (Fig. 2b).The human homolog, B 0 AT1, is encoded by the predicted locus SLC6A19, with a 2,022-bp open reading frame. PCR amplification using human kidney cDNA produced a 1,905-bp product with 100% identity to SLC6A19 sequence. We next determined the genomic organization of SLC6A19, which has a stop codon 28 bases before the ATG in the 5¢ untranslated region. SLC6A19 has 12 coding exons. The B 0 AT1 protein contains 634 amino acids and 12 predicted transmembrane regions (Fig. 1b). In a panel of human cDNAs, we detected robust expression of SLC6A19 in kidney and small intestine, with minimal expression in pancreas (Fig. 2c). SLC6A19 was also expressed in stomach, liver, duodenum and ileocecum (data n...

Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction. Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS. Over the last 5 years, we have evaluated six subjects with the clinical diagnosis of AAAS. Three subjects had mutations in the AAAS gene-- including one novel mutation (IVS8+1 G>A)-- and a broad spectrum of clinical presentations. However, three subjects with classic AAAS did not have mutations in the AAAS gene on both alleles. This finding supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded.

BackgroundTriple-A syndrome (Allgrove syndrome) is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and – occasionally – autonomic instability. Mutations have been found in the AAAS gene on 12q13.Case presentationWe present the case of a 12 year-old boy with classic systemic features of triple-A syndrome and several prominent ophthalmic features, including: accommodative spasm, dry eye, superficial punctate keratopathy, and pupillary hypersensitivity to dilute pilocarpine. MRI showed small lacrimal glands bilaterally. DNA sequencing of PCR-amplified fragments from the 16 exons of the AAAS gene revealed compound heterozygosity for a new, out-of-frame 5-bp deletion in exon 15, c1368-1372delGCTCA, and a previously-described nonsense mutation in exon 9, c938C>T, R286X.ConclusionsIn addition to known ophthalmic manifestations, triple-A syndrome can present with accommodative dysregulation and ocular signs of autonomic dysfunction.