Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.
Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.
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DOI：
10.1111/bjd.17388
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发表时间：
2019-05
期刊：
影响因子：
--
通讯作者：
Kelsell DP
中科院分区：
文献类型：
--
作者：
Maruthappu T;Posafalvi A;Castelletti S;Delaney PJ;Syrris P;O'Toole EA;Green KJ;Elliott PM;Lambiase PD;Tinker A;McKenna WJ;Kelsell DP
心律失常性心肌病（AC）是一种遗传性疾病，经常诊断不足，易导致心脏性猝死。AC的罕见隐性形式可与羊毛状毛发和掌跖角化病相关，但大多数常染色体显性AC形式已报告为心脏特异性。致病突变经常发生在桥粒基因，包括桥粒斑蛋白（DSP）在这项研究中，我们系统地研究了存在皮肤和头发表型的杂合桥粒斑蛋白（DSP）突变携带者与AC。通过详细的临床检查（心脏、毛发和皮肤）和分子表型分析，对6个AC家系的38名DSP显性功能缺失（无义或移码）突变携带者进行了评估。所有携带影响两种主要DSP亚型（DSP I和II）的突变的携带者在检查的家系中均观察到卷曲或波浪状头发，但家族6的成员除外，其中突变的位置仅影响心脏特异性亚型DSP I。轻度掌跖角化病也存在于许多载体。来自非病变携带者皮肤的cDNA的桑格测序表明突变等位基因的降解。患者皮肤的免疫组织化学显示DSP和其他连接蛋白（斑珠蛋白，连接蛋白43）在基底表皮中的错误定位。然而，在系列6中，DSP定位与对照皮肤相当。这项研究确定了一个高度可识别的皮肤表型与显性，功能丧失DSPI/II突变的基础AC。在没有明显心脏特征的情况下，提高医护人员对这种表型的认识有助于及时诊断AC。
Arrhythmogenic Cardiomyopathy (AC) is an inherited, frequently under diagnosed disorder, predisposing 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 as cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP) In this study, we have systematically investigated the presence of a skin and hair phenotype in heterozygous desmoplakin (DSP) mutation carriers with AC. 6 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 (DSP I 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, DSP I. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from non-lesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalisation of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localisation was comparable to 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 amongst healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.
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影响因子：
3.6
作者：
Loussouarn, Genevieve;Garcel, Anne-Lise;de la Mettrie, Roland
通讯作者：
de la Mettrie, Roland
影响因子：
39.3
作者：
Marcus, Frank I.;McKenna, William J.;Zareba, Wojciech
通讯作者：
Zareba, Wojciech
影响因子：
3.5
作者：
Norgett, EE;Hatsell, SJ;Kelsell, DP
通讯作者：
Kelsell, DP
影响因子：
24
作者：
Sen-Chowdhry, Srijita;Syrris, Petros;McKenna, William J.
通讯作者：
McKenna, William J.
影响因子：
3.6
作者：
Broussard, Joshua A.;Getsios, Spiro;Green, Kathleen J.
通讯作者：
Green, Kathleen J.