Zhang Zhao, Quinlan Jackie, Hoy Wendy, Hughson Michael D, Lemire Mathieu, Hudson Thomas, Hueber Pierre-Alain, Benjamin Alice, Roy Anne, Pascuet Elena, Goodyer Meigan, Raju Chandhana, Houghton Fiona, Bertram John, Goodyer Paul
McGill University Health Centre Research Institute, Montreal Quebec, Canada.
J Am Soc Nephrol. 2008 Oct;19(10):2027-34. doi: 10.1681/ASN.2007101098.
Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10% smaller and cord blood cystatin C levels 9% higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.
正常人群中先天性肾单位数量相差五倍，处于该范围下限的个体一生中患原发性高血压或肾功能不全的风险可能会增加；然而，决定肾单位数量的机制尚不清楚。本研究检验了一种假说，即RET基因的常见低表达变异体可能导致一些正常新生儿出现轻微肾发育不全，RET基因编码一种对肾分支形态发生至关重要的酪氨酸激酶受体。在第7外显子的一个外显子剪接增强子内鉴定出一种常见的单核苷酸多态性（rs1800860 G/A）。mRNA位置1476处的腺苷变异体降低了对剪接体蛋白的亲和力，增加了异常mRNA剪接的可能性，并降低了人类细胞中功能性转录本的水平。在体内，携带rs1800860（1476A）等位基因的正常白人新生儿的肾脏体积比携带rs1800860（1476G）等位基因的新生儿小10%，脐带血胱抑素C水平高9%。这些发现表明，RET（1476A）等位基因与其他常见的多态性发育基因相结合，可能在很大一部分白人中导致轻微肾发育不全。这种基因变异是否会影响临床结果需要进一步研究。
