Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters
Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters
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DOI：
10.1172/jci36625
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发表时间：
2008-12-01
影响因子：
15.9
通讯作者：
Rasko, John E. J.
中科院分区：
文献类型：
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作者：
Broeer, Stefan;Bailey, Charles G.;Rasko, John E. J.
亚氨基甘氨酸尿症 (IG) 是甘氨酸、亚氨基酸脯氨酸和羟脯氨酸肾脏运输的常染色体隐性异常，但具体的遗传缺陷尚未确定。同样，尽管不伴有亚氨基酸尿症的相关疾病高甘氨酸尿症 (HG) 被归因于假定的甘氨酸、脯氨酸和羟脯氨酸转运蛋白缺陷的杂合性，但确认潜在的遗传缺陷仍然很困难。在这里，我们对通过新生儿 IG 筛查项目首次发现的 7 个家庭应用了候选基因测序方法。遗传和功能研究均确定编码质子氨基酸转运蛋白 SLC36A2 (PAT2) 的基因是这些家族中负责 IG 的主要基因，其遗传与经典的半显性模式一致，其中 2 个遗传非功能等位基因赋予 IG 表型，而 I 非功能等位基因足以赋予 HG 表型。保留残余转运活性的 SLC36A2 突变与编码亚氨基酸转运蛋白 SLC6A20 (IMINO) 的基因突变相结合，导致 IG 表型。在 IG 或 HG 家族中，编码假定的甘氨酸转运蛋白 SLC6A18 (XT2) 和中性氨基酸转运蛋白 SLC6A19 (B(0)AT1) 的基因中发现了其他突变，表明编码这些转运蛋白的基因中的突变也可能导致这些表型。总之，虽然 IG 和 HG 被认为是明显简单的孟德尔疾病，但它们表现出复杂的分子解释，具体取决于主要基因和伴随的修饰基因。
Iminoglycinuria (IG) is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while I nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B(0)AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes.