Boutros Marylise, Vicanek Caroline, Rozen Rima, Goodyer Paul
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Kidney Int. 2005 Feb;67(2):443-8. doi: 10.1111/j.1523-1755.2005.67100.x.
Cystinuria is an inherited disorder of luminal reabsorptive transport for cystine and dibasic amino acids in the renal proximal tubule. Two cystinuria genes have been identified. Mutations of SLC7A9, which encodes the luminal transport channel itself, tend to be dominant and mutations of SLC3A1 (rBAT), which encodes a transporter subunit, are always recessive. Patients who inherit two recessive mutations or two dominant mutations have equally severe forms of cystinuria. Heterozygotes excrete cystine in the normal (type I), moderate (type III), or high stone-forming (type II) range.
Infants with cystinuria were identified via the Quebec Newborn Urinary Screening Program. In a subgroup of these infants, cystinuria was severe in the first months of life, but partially resolved by 2 to 4 years postnatally. We assigned each patient a final cystinuria phenotype at 3 to 4 years. In addition, we characterized SLC3A1 gene expression in fetal and postnatal human kidney.
Most infants with transient neonatal cystinuria are eventually classified as type III heterozygotes. All infants with mutant cystinuria genes have exaggerated neonatal cystine excretion except those who inherit two SLC3A1 mutations (type I/I cystinuria); these children have persistent severe cystinuria, implying that wildtype SLC3A1 is required for the maturational effect. Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney.
Maturation of SLC3A1 gene expression between midgestation and 4.5 years postnatal age may account for transient neonatal cystinuria.
胱氨酸尿症是一种遗传性疾病，影响肾近端小管中胱氨酸和二碱基氨基酸的管腔重吸收转运。已鉴定出两个胱氨酸尿症基因。编码管腔转运通道本身的SLC7A9发生的突变往往呈显性，而编码转运蛋白亚基的SLC3A1（rBAT）发生的突变总是隐性的。继承两个隐性突变或两个显性突变的患者患有同样严重形式的胱氨酸尿症。杂合子排泄的胱氨酸处于正常（I型）、中度（III型）或高结石形成风险（II型）范围。
通过魁北克新生儿尿液筛查项目识别患有胱氨酸尿症的婴儿。在这些婴儿的一个亚组中，胱氨酸尿症在出生后的头几个月很严重，但在出生后2至4岁时部分缓解。我们在3至4岁时为每位患者确定最终的胱氨酸尿症表型。此外，我们对胎儿和出生后人类肾脏中的SLC3A1基因表达进行了表征。
大多数短暂性新生儿胱氨酸尿症婴儿最终被归类为III型杂合子。所有患有突变型胱氨酸尿症基因的婴儿，除了那些继承两个SLC3A1突变的婴儿（I/I型胱氨酸尿症）外，新生儿期胱氨酸排泄量都会增加；这些儿童患有持续性严重胱氨酸尿症，这意味着野生型SLC3A1对成熟效应是必需的。发现SLC3A1 mRNA在出生后肾脏中的表达比胎儿肾脏高十倍；近端小管转录因子PAX8使SLC3A1表达增加一倍。rBAT在胎儿和成人肾脏的近端曲管和直小管中均有表达。
妊娠中期至出生后4.5岁之间SLC3A1基因表达的成熟可能是短暂性新生儿胱氨酸尿症的原因。
