Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma
Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma
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DOI：
10.1093/hmg/8.1.143
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发表时间：
1999-01-01
影响因子：
3.5
通讯作者：
Hughes, AE
中科院分区：
文献类型：
--
作者：
Keith, D;Armstrong, B;Hughes, AE
桥粒是高度组织化的细胞间粘附连接，其在表皮和经历机械应力的其他组织中特别突出。桥粒斑蛋白是桥粒斑的组成成分，是存在于这种连接中的最丰富的蛋白质，并且在这些组织中将中间丝网络连接到质膜中起关键作用。在这里，我们报告的第一个突变基因编码桥粒斑蛋白。在显性遗传性皮肤病条纹状掌跖角化病家系的基因组DNA中观察到了导致无效等位基因和单倍不足的突变。受影响的个人有一个线性模式的皮肤增厚的手指和手掌和皮肤增厚的局限性领域的鞋底。受影响的皮肤表现出松动的细胞间连接，破坏桥粒角蛋白中间丝的相互作用和一定比例的基本桥粒结构。该疾病定位于染色体6p 21，最大lod值为10.67。该突变是桥粒斑蛋白基因外显子4中的杂合性C->T转换，并预测肽的N-末端区域中的提前终止密码子。这是第一个报道的桥粒斑蛋白突变，也是第一个涉及结构成分单倍不足的遗传性皮肤病。它将桥粒斑蛋白的剂量确定为维持表皮完整性的关键。
Desmosomes are highly organized intercellular adhesive junctions that are particularly prominent in epidermis and other tissues experiencing mechanical stress. Desmoplakin, a constitutive component of the desmosomal plaque, is the most abundant protein present in such junctions and plays a critical role in linking the intermediate filament network to the plasma membrane in these tissues. Here we report the first mutation in the gene encoding desmoplakin. The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma. Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67. The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide. This is the first reported mutation of desmoplakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity.