Dentin phosphoprotein frameshift mutations in hereditary dentin disorders and their variation patterns in normal human population
Dentin phosphoprotein frameshift mutations in hereditary dentin disorders and their variation patterns in normal human population
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DOI：
10.1136/jmg.2007.056911
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发表时间：
2008-07-01
影响因子：
4
通讯作者：
Bian, Z.
中科院分区：
文献类型：
--
作者：
Song, Y. L.;Wang, C. N.;Bian, Z.
背景：牙本质磷酸蛋白(DPP)是牙本质中含量最丰富的非胶原蛋白，具有高度的磷酸化作用，在牙本质的生物矿化过程中起着关键作用。在大多数受影响的家庭中，孤立的遗传性牙本质疾病的病因在很大程度上是未知的，DPP和牙本质疾病之间的联系也没有很好地建立起来。本研究旨在确定遗传性牙本质病中是否存在DPP突变，并阐明正常人群中DPP的序列变异模式。方法：对8个遗传性牙本质病家系和110名正常人群的基因组DNA进行分析。通过聚合酶链式反应(PCR)扩增出DPP的全长编码序列，并通过直接测序和Topo TA克隆测序筛选突变和变异。结果：在8个家系中的5个家系中检测到5个DPP编码区移码突变。这些突变在受影响的家系中与疾病表型共分离，在220条对照染色体中没有发现。在正常人群中，我们在DPP编码区发现了14个框内插入/缺失(插入/缺失)、6个非同义单核苷酸多态(SNPs)和5个同义SNPs。这些变异在被调查的正常人群中表现出广泛的连锁不平衡，总共构成了15种单倍型和3种优势单倍型。结论：我们的数据首次提供了DPP突变可以导致遗传性牙本质疾病的证据，并提示DPP的框内长度变异和错义SNPs对牙本质的形成没有明显的致病作用。
Background: Dentin phosphoprotein ( DPP) is the most abundant non-collagenous protein in dentin, which is highly phosphorylated and plays key roles in dentin biomineralisation. The aetiology of isolated hereditary dentin disorders in most affected families is largely unknown and the association between DPP and dentin disorders has not been well established. This study aims to determine whether there are some involvements for DPP mutations in inherited dentin disorders and to clarify the sequence variation patterns of DPP in normal population.Methods: Genomic DNA was analysed in eight families with hereditary dentin disorders and 110 individuals in the normal population. The full coding sequence of DPP was amplified by polymerase chain reaction (PCR) and screened for mutations and variations by direct sequencing and TOPO TA-cloning sequencing.Results: Five frameshift mutations in DPP coding region were identified in five of the eight families. The mutations co-segregated with the disease phenotypes in affected families and were not found in 220 control chromosomes. In the normal population, we revealed 14 in-frame indels (insertion/deletion), six non-synonymous single nucleotide polymorphisms ( SNPs), and five synonymous SNPs in the DPP coding region. These variants display extensive linkage disequilibrium and constitute a total of 15 haplotypes with three predominant haplotypes in the investigated normal population.Conclusions: Our data provide the first evidence that DPP mutations can cause hereditary dentin disorders and suggest that in-frame length variations and missense SNPs in DPP have no obvious pathogenetic effects on dentin formation.