Hendig Doris, Schulz Veronika, Eichgrün Jutta, Szliska Christiane, Götting Christian, Kleesiek Knut
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik , der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany.
J Mol Med (Berl). 2005 Feb;83(2):140-7. doi: 10.1007/s00109-004-0588-2. Epub 2004 Nov 10.
Pseudoxanthoma elasticum (PXE; OMIM 177850 and 264800) is a rare heritable disorder of the connective tissue affecting the extracellular matrix of the skin, eyes, gastrointestinal system, and cardiovascular system. It has recently been found that mutations in the ABCC6 gene encoding the multidrug resistance-associated protein (MRP) 6 cause PXE. This study examined novel mutations in the ABCC6 gene in our cohort of 76 German PXE patients and 54 unaffected or not yet affected relatives with a view to expanding the known mutational spectrum of the gene. Mutational analysis was performed using denaturing high-performance liquid chromatography and direct sequencing. The mutational screening revealed a total of 22 different ABCC6 sequence variations. We identified seven novel and four previously described PXE-associated mutations as well as eight novel neutral ABCC6 sequence variants. The new PXE-associated mutations included five missense mutations, one single base pair deletion, and one larger out-of-frame deletion. We suspect that the novel missense mutations lead to an impaired function of MRP6. Both deletions are predicted to result in a dysfunctional MRP6 protein. The seven new ABCC6 mutations were not present in 200 alleles from healthy blood donors which served as a control cohort. Most of the PXE patients who were found to carry PXE-causing ABCC6 mutations were assumed to manifest the PXE phenotype because of a compound heterozygous genotype. However, a genotype-phenotype correlation could not be established for the detected ABCC6 mutations. In summary, our data give a further insight into the spectrum of ABCC6 mutations in PXE patients.
弹性假黄瘤（PXE；OMIM 177850和264800）是一种罕见的结缔组织遗传性疾病，会影响皮肤、眼睛、胃肠道系统和心血管系统的细胞外基质。最近发现，编码多药耐药相关蛋白（MRP）6的ABCC6基因突变会导致PXE。本研究检测了我们队列中76名德国PXE患者和54名未受影响或尚未受影响亲属的ABCC6基因新突变，以期扩大该基因已知的突变谱。使用变性高效液相色谱和直接测序进行突变分析。突变筛查共发现22种不同的ABCC6序列变异。我们鉴定出7个新的和4个先前描述的与PXE相关的突变，以及8个新的中性ABCC6序列变异。新的与PXE相关的突变包括5个错义突变、1个单碱基对缺失和1个较大的框外缺失。我们怀疑新的错义突变会导致MRP6功能受损。预计这两个缺失都会导致MRP6蛋白功能失调。作为对照队列的200名健康献血者的等位基因中未发现这7个新的ABCC6突变。大多数被发现携带导致PXE的ABCC6突变的PXE患者被认为由于复合杂合基因型而表现出PXE表型。然而，对于检测到的ABCC6突变，无法建立基因型与表型的相关性。总之，我们的数据进一步深入了解了PXE患者中ABCC6突变的谱。
