Homozygous alpha 6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia
Homozygous alpha 6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia
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DOI：
10.1093/hmg/6.5.669
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发表时间：
1997-05-01
影响因子：
3.5
通讯作者：
Uitto, J
中科院分区：
文献类型：
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作者：
Pulkkinen, L;Kimonis, VE;Uitto, J
先天性幽门或十二指肠闭锁的交界性大疱性表皮样囊肿是这组常染色体隐性遗传性水疱性皮肤病中的一种独特变异。在本研究中，我们首次证实了在一个有三个患病个体的家族中α 6整合素基因（ITGA 6）的纯合突变。为此，我们首先确定了ITGA 6的基因组结构，并通过高分辨率辐射杂交作图将该基因定位于染色体2 q，对含有ITGA 6的单个外显子的PCR产物进行异源双链分析，随后进行直接核苷酸测序，结果表明，先证者是纯合子的G到T颠换在+1位置的内含子12。该突变1856+1G-->T影响5'供体剪接位点的不变碱基，预测涉及外显子12的异常剪接。通过限制性内切酶消化证实了先证者DNA中的突变，这也证实了父母是该突变的杂合携带者。α 6整合素的表达改变，其在真皮-表皮连接处与β 4亚基形成异二聚体，可以解释皮肤轻微创伤导致的脆性和起泡。
Junctional epidermolysis bullosa with congenital pyloric or duodenal atresia is a distinct variant within this group of autosomal recessive blistering skin diseases. In this study we demonstrate, for the first time, a homozygous mutation in the alpha 6 integrin gene (ITGA6) in a family with three affected individuals, For this purpose, we first determined the genomic organization of ITGA6, and placed the gene on chromosome 2q by high resolution radiation hybrid mapping, Heteroduplex analysis of PCR products containing the individual exons of ITGA6, followed by direct nucleotide sequencing, revealed that the proband was homozygous for a G-to-T transversion in the +1 position of intron 12. This mutation, 1856+1G-->T, affects an invariant base of the 5' donor splice site predicting aberrant splicing involving exon 12. The mutation was verified in the proband's DNA by restriction enzyme digestion which also confirmed that the parents were heterozygous carriers of this mutation, Altered expression of alpha 6 integrin, which forms a heterodimer with the beta 4 subunit at the dermal-epidermal junction, would explain fragility and blistering as a result of minor trauma to the skin.