Molecular mechanisms determining severity in patients with Pierson syndrome
Molecular mechanisms determining severity in patients with Pierson syndrome
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DOI：
10.1038/s10038-019-0715-0
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发表时间：
2020-01-21
影响因子：
3.5
通讯作者：
Nozu, Kandai
中科院分区：
文献类型：
--
作者：
Minamikawa, Shogo;Miwa, Saori;Nozu, Kandai
LAMB 2中的突变体导致皮尔逊综合征（PS），一种严重的先天性肾病综合征，伴有眼部和神经系统缺陷。患者的肾脏标本显示肾小球基底膜（GBM）层粘连蛋白β 2表达完全阴性。相反，LAMB 2中层粘连蛋白N-末端（LN）结构域外的错义变体导致较温和的表型。然而，我们经历的病例没有显示这些典型的基因型-表型相关性。在本文中，我们报告了6例PS患者：4例轻度表型和2例重度表型。我们进行了分子研究，包括蛋白质表达和转录分析。结果显示，4例轻度表型患者中有3例的错义突变位于LN结构域之外，2例重度PS患者中有1例的错义突变位于LN结构域;这些突变位置可以解释其表型。然而，一个轻度病例具有剪接位点变异（c.3797 + 5G>A），这应该与严重表型相关。在转录物分析后，该变体产生了一些不同大小的转录物，包括完全正常的转录物，这可能赋予了较温和的表型。在一个严重的情况下，我们检测到位于LN结构域之外的c.4616G>A的单核苷酸取代，这应该与较轻的表型相关。然而，我们检测到异常剪接所造成的创建一个新的剪接位点由这个单碱基取代。这些是导致非典型基因型-表型相关性的新机制。此外，所有4例轻度表型病例均显示GBM上层粘连蛋白β 2表达。我们确定了新的机制，导致非典型的基因型-表型相关的PS。
Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin beta 2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin beta 2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.