Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum
Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum
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DOI：
10.1086/318807
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发表时间：
2001-03-01
影响因子：
9.8
通讯作者：
Pulkkinen, L
中科院分区：
文献类型：
--
作者：
Ringpfeil, F;Nakano, A;Pulkkinen, L
弹性假性黄瘤（PXE）是一种影响皮肤、眼睛和心血管系统弹性结构的全身性遗传性疾病，具有相当高的发病率和死亡率。最近，编码多药耐药蛋白6 （MRP6）的ABCC6基因（也称为“MRP6”或“eMOAT”）发生突变，MRP6被认为是一种功能未知的跨膜ABC转运蛋白。迄今为止所描述的大多数遗传病变由单碱基对取代导致无义、错义或剪接位点突变组成。在这项研究中，我们研究了四个常染色体隐性遗传PXE的多重家族。在每个家庭中，先证者都是一个单碱基对替代突变的复合杂合子和一个新的，类似于16.5 kb的缺失突变，跨越反式中单碱基对替代的位点。缺失突变显示从内含子22延伸到内含子29，导致相应mRNA的1213个核苷酸框外缺失，MRP6多肽的505个氨基酸被消除。在不同种族背景的4个家族中，缺失断点完全相同，13个微卫星标记的单倍型分析表明，缺失是独立发生的。内含子22和29的缺失断点嵌入在AluSx重复序列中，特别是在16bp的DNA片段中，表明alu介导的同源重组是一种机制。
Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder affecting the elastic structures in the skin, eyes, and cardiovascular system, with considerable morbidity and mortality. Recently, mutations in the ABCC6 gene (also referred to as "MRP6" or "eMOAT") encoding multidrug-resistance protein 6 (MRP6), a putative transmembrane ABC transporter protein of unknown function, have been disclosed. Most of the genetic lesions delineated thus far consist of single-base-pair substitutions resulting in nonsense, missense, or splice-site mutations. In this study, we examined four multiplex families with PXE inherited in an autosomal recessive pattern. In each family, the proband was a compound heterozygote for a single-base-pair-substitution mutation and a novel, similar to 16.5-kb deletion mutation spanning the site of the single-base-pair substitution in trans. The deletion mutation was shown to extend from intron 22 to intron 29, resulting in out-of-frame deletion of 1,213 nucleotides from the corresponding mRNA and causing elimination of 505 amino acids from the MRP6 polypeptide. The deletion breakpoints were precisely the same in all four families, which were of different ethnic backgrounds, and haplotype analysis by 13 microsatellite markers suggested that the deletion had occurred independently. Deletion breakpoints within introns 22 and 29 were embedded within AluSx repeat sequences, specifically in a 16-bp segment of DNA, suggesting Alu-mediated homologous recombination as a mechanism.