A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum
A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum
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DOI：
10.1086/323704
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发表时间：
2001-10-01
影响因子：
9.8
通讯作者：
Boyd, CD
中科院分区：
文献类型：
--
作者：
Le Saux, O;Beck, K;Boyd, CD
为了更好地了解弹性假性黄瘤（PXE）的发病机制，我们对122例无亲缘关系的PXE患者进行了atp结合盒亚家族C成员6 （ABCC6）的突变分析，这是迄今为止研究的最大的患者队列。36个突变被描述为特征，其中28个是新的变体（迄今为止已知的43个PXE突变）。21个等位基因是错义变异，6个是小插入或缺失，5个是无义变异，2个是可能导致mRNA剪接异常的等位基因，2个是涉及ABCC6的大缺失。虽然大多数突变似乎是独特的变异，但两种致病等位基因经常出现在明显无关的个体中。R1141X在我们的患者队列中发现的频率为18.8%，在欧洲患者中占优势。ABCC6del23-29的发生率为12.9%，在美国患者中普遍存在。这些结果表明，R1141X和ABCC6del23-29可能在区域上来源于创始等位基因。在研究的244条染色体中，有64%的人发现了可能的致病突变，在122名患者中，85.2%的人发现至少有一个致病等位基因。我们的研究结果表明，部分未检测到的突变等位基因可能是基因组重排或发生在ABCC6基因非编码区域的突变。ABCC6突变的分布模式显示，在编码大c端胞质环的外显子和c端核苷酸结合域（NBD2）内存在一组致病变异。我们在PXE表型和ABCC6功能之间的复杂关系的背景下讨论了这种突变模式的潜在结构和功能意义。
To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6del23-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in similar to 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.