Puomila Kirsi, Simell Olli, Huoponen Kirsi, Mykkänen Juha
Department of Medical Genetics, Institute of Biomedicine, University of Turku, Turku, Finland.
Mol Genet Metab. 2007 Mar;90(3):298-306. doi: 10.1016/j.ymgme.2006.11.007. Epub 2006 Dec 29.
The human SLC7A7 gene encodes y(+)L amino acid transporter-1 (y(+)LAT-1). Mutations in the SLC7A7 coding region cause a rare recessive disorder, lysinuric protein intolerance (LPI). LPI is enriched in the Finnish population, where all patients carry the same homozygous founder mutation. Although the same LPI genotype is present in all patients, clinical symptoms vary greatly and thus show no genotype-phenotype correlation. In LPI, the transport of cationic amino acids is functionally affected at least at the basolateral membrane of the polarised epithelial cells in the kidney tubules and small intestine, although SLC7A7 is expressed much more widely. Interestingly, some LPI patients' tissues exhibit normal cationic amino acid transport despite the mutations leading to clinical phenotype. When studying the various manifestations of this monogenic disorder and the tissue specificity of the transport defect, it is crucial to know the transcriptional regulatory mechanisms of SLC7A7 gene. In this study, we have identified a novel alternative, TATA-box-containing promoter that plays a role in the tissue-specific regulation of the SLC7A7 gene expression. This newly found downstream promoter in front of exon 2 seems to be active in tissues with strong defects in the function of the transporter in patients with LPI.
人类SLC7A7基因编码γ(+)L氨基酸转运体-1（γ(+)LAT-1）。SLC7A7编码区的突变会导致一种罕见的隐性疾病——赖氨酸尿性蛋白不耐受症（LPI）。LPI在芬兰人群中较为常见，所有患者都携带相同的纯合始祖突变。尽管所有患者的LPI基因型相同，但临床症状差异很大，因此不存在基因型与表型的相关性。在LPI中，阳离子氨基酸的转运至少在肾小管和小肠中极化上皮细胞的基底外侧膜上受到功能影响，尽管SLC7A7的表达更为广泛。有趣的是，一些LPI患者的组织尽管存在导致临床表型的突变，但仍表现出正常的阳离子氨基酸转运。在研究这种单基因疾病的各种表现和转运缺陷的组织特异性时，了解SLC7A7基因的转录调控机制至关重要。在本研究中，我们鉴定出了一种新的、含有TATA框的可变启动子，它在SLC7A7基因表达的组织特异性调控中发挥作用。这个新发现的位于外显子2之前的下游启动子似乎在LPI患者中转运体功能存在严重缺陷的组织中具有活性。
