由编码rBAT亚基（bo，+AT）的SLC7A9基因突变引起的非I型胱氨酸尿症。

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

作者信息

Feliubadaló L, Font M, Purroy J, Rousaud F, Estivill X, Nunes V, Golomb E, Centola M, Aksentijevich I, Kreiss Y, Goldman B, Pras M, Kastner D L, Pras E, Gasparini P, Bisceglia L, Beccia E, Gallucci M, de Sanctis L, Ponzone A, Rizzoni G F, Zelante L, Bassi M T, George A L, Manzoni M, De Grandi A, Riboni M, Endsley J K, Ballabio A, Borsani G, Reig N, Fernández E, Estévez R, Pineda M, Torrents D, Camps M, Lloberas J, Zorzano A, Palacín M

机构信息

Centre de Genètica Mèdica i Molecular (IRO), Hospital Duran i Reynals, Autovía de Castelldefels Km 2.7, L'Hospitalet de Llobregat, Barcelona, E-08907, Spain.

出版信息

Nat Genet. 1999 Sep;23(1):52-7. doi: 10.1038/12652.

DOI:10.1038/12652

PMID:10471498

Abstract

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

摘要

胱氨酸尿症（MIM 220100）是一种常见的隐性疾病，表现为肾脏对胱氨酸和二碱基氨基酸的重吸收障碍。编码rBAT的SLC3A1基因突变会导致I型胱氨酸尿症（参考文献1），但不会引发其他类型的胱氨酸尿症（参考文献2）。通过连锁分析已将一个其突变导致非I型胱氨酸尿症的基因定位到19q12 - 13.1（参考文献3,4）。我们鉴定出一种新的转录本，它编码一种蛋白质（bo，+AT，即bo，+氨基酸转运体），该蛋白质属于氨基酸转运体轻链亚基家族，在肾脏、肝脏、小肠和胎盘中表达，并将其基因（SLC7A9）定位到非I型胱氨酸尿症的19q位点。将bo，+AT与rBAT共转染可使rBAT转运至质膜，并导致COS细胞摄取L - 精氨酸。我们在利比亚犹太人、北美、意大利和西班牙的非I型胱氨酸尿症患者中发现了SLC7A9突变。利比亚犹太患者对于一个奠基者错义突变（V170M）是纯合的，当在COS细胞中与rBAT共转染时，该突变会消除bo，+AT的氨基酸摄取活性。我们在其他患者中鉴定出四个错义突变（G105R、A182T、G195R和G295R）以及两个移码突变（520insT和596delTG）。我们的数据证实SLC7A9突变会导致非I型胱氨酸尿症，并表明bo，+AT是rBAT的轻链亚基。