Functional characterization of LMX1B mutations associated with nail-patella syndrome
Functional characterization of LMX1B mutations associated with nail-patella syndrome
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DOI：
10.1203/01.pdr.0000157674.63621.2c
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发表时间：
2005-06-01
影响因子：
3.6
通讯作者：
Igarashi, T
中科院分区：
文献类型：
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作者：
Sato, U;Kitanaka, S;Igarashi, T
指甲-髌骨综合征(NPS)是一种常染色体显性遗传病，以指甲发育不良、髌骨缺失或发育不良、肘关节发育不良和肾病为特征。最近的研究表明，NPS是LIM同源结构域基因Lmx1b杂合突变的结果。随后，在NPS患者中报道了Lmx1b基因的许多突变。然而，对突变蛋白质的功能分析只在少数几个突变中进行。此外，人类显性遗传的机制尚未建立。在本研究中，我们分析了三例日本NPS患者的Lmx1b基因，发现了两个新的突变，6个核苷酸缺失(Delta 246N 247Q)和V242L。这两个突变位于Lmx1b的同源区域。对Lmx1b突变体的功能分析表明，这些突变体的转录活性降低，并失去了DNA结合能力。此外，我们还证明了每个突变体对野生型Lmx1b的转录活性没有表现出显性-负性效应。这些结果表明，NPS是由Lmx1b功能缺失突变引起的，Lmx1b单倍性不足可能是NPS的主要发病机制。
Nail-patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephropathy. Recently, it was shown that NPS is the result of heterozygous mutations in the LIM-homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B gene have been reported in NPS patients. However, functional analyses of the mutant proteins have been performed in only a few mutations. Furthermore, the mechanisms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and identified two novel mutations, 6 nucleotide deletion (Delta 246N 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B. Functional analyses of the LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant-negative effect on the transcriptional activity of wild-type LMX1B. These results suggested that NPS is caused by loss-of-function mutations of LMX1B, and haploinsufficiency of LMX1B should be the predominant pathogenesis of NPS in humans.