Blizard Institute, Queen Mary University of London, London, U.K.
Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
Br J Dermatol. 2019 May;180(5):1114-1122. doi: 10.1111/bjd.17388. Epub 2019 Jan 2.
Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP).
In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC.
Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping.
All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin.
This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.
致心律失常性右室心肌病（AC）是一种遗传性疾病，常常被漏诊，可导致个体发生心源性猝死。罕见的隐性 AC 形式可与羊毛状发和掌跖角化过度症相关，但大多数常染色体显性 AC 形式已被报道为心脏特异性。致病突变常发生在桥粒蛋白基因中，包括桥粒斑蛋白（DSP）。
本研究系统性地研究了 AC 患者中携带杂合型 DSP 突变的个体是否存在皮肤和毛发表型。
通过详细的临床检查（心脏、毛发和皮肤）和分子表型分析，评估了 6 个具有 DSP 显性失活（无义或移码）突变的 AC 家系，共 38 名携带者。
除了 6 号家族的成员外，所有携带影响主要 DSP 同工型（DSP1 和 II）的突变的携带者均表现出卷发或波浪发，6 号家族中的突变仅影响心脏特异性同工型 DSP1。许多携带者还存在轻度掌跖角化过度症。非病变部位携带者皮肤的 cDNA Sanger 测序提示突变等位基因降解。患者皮肤的免疫组化显示 DSP 和其他连接蛋白（桥粒斑蛋白、连接蛋白 43）在基底层的定位异常。然而，在 6 号家族中，DSP 的定位与对照皮肤相似。
本研究确定了一种与 AC 相关的显性失活 DSP1/2 突变相关的高度可识别的皮肤表型。如果没有明显的心脏特征，提高医疗保健工作者对这种表型的认识可以促进 AC 的及时诊断。
