Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders
Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders
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DOI：
10.1038/sj.ki.5001679
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发表时间：
2006-09-01
影响因子：
19.6
通讯作者：
Hildebrandt, F.
中科院分区：
文献类型：
--
作者：
Hasselbacher, K.;Wiggins, R. C.;Hildebrandt, F.
先天性肾病综合征具有临床和遗传异质性。大多数病例可归因于NPHS1、NPHS2和WT1基因的突变。通过对一个患有孤立性先天性肾病综合征的近亲家族进行纯合子定位，我们在染色体3p上发现了一个潜在的候选区域。最近报道的Pierson综合征（microcoria-先天性肾病综合征；omim# 609049）中发生突变的LAMB2基因位于连锁区间。LAMB2所有编码外显子的测序显示，在两名受影响的儿童中都有一种新的纯合错义突变（R246Q）。这个密码子（R246W）的另一个突变，在进化过程中高度保守，最近被报道导致Pierson综合征。随后在另外6个先天性肾病综合征家族中进行LAMB2突变筛查，发现一个家族中有两个新的错义突变存在复合杂合性，并伴有非特异性眼部异常。这些发现表明，lamb2相关疾病的范围比先前预期的更广泛，包括没有眼睛异常的先天性肾病综合征或与Pierson综合征不同的轻微眼部变化。这种表型变异可能反映了特定的基因型。我们得出结论，如果在NPHS1、NPHS2或WT1中未发现突变，则应考虑在先天性肾病综合征中进行LAMB2突变分析。
Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1.