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Abstract：
Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997.
To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019.
Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections.
These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.
To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019.
Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections.
These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.
摘要：
桥粒是细胞间钙粘蛋白介导的粘附复合物，可将中间细丝锚定到细胞膜上，并且是机械应力下组织强粘附所必需的。桥粒的一个特定成分是plakophilin1（PKP1），主要表现在表皮的棘层。PKP1的功能缺失常染色体隐性突变导致外胚层发育不良-皮肤脆性(EDSF)综合征,最初的遗传性孟德尔病桥粒在1997年首次报道。
调查1997-2019年2例新发的EDSF综合征病例，并对致病性PKP1突变进行文献复习。
PKP1的Sanger测序鉴定出两个新的纯合移码突变：c.409_410insAC（p。thr137thrfs*61）和c.1213delA（p。Arg411Glufs*22）。对18例双等位基因PKP1基因突变的患者进行综合分析，但不是一个马赛克病例或6个缺乏基因突变研究的额外病例。所有致病性种系突变均为功能丧失（剪接位点，移码,无义）内含子1共有受体剪接位点的突变（c.203-1>A或G>T）代表复发性发现。所有受影响的个体都存在皮肤脆性和指甲受累(18/18)，大多数病例显示掌plant角化病（16/18），脱发/毛发减少（16/18）和口周裂痕/唇炎（12/15；3例未评论）。一些人的进一步观察包括瘙痒，未能在低身高/体重百分位数的情况下茁壮成长，毛囊角化过度,多汗症,行走困难,牙列发育不良和复发性胸部感染。
这些数据扩展了EDSF综合征的分子基础，并有助于定义这种桥粒遗传病的原型和可变表现。
调查1997-2019年2例新发的EDSF综合征病例，并对致病性PKP1突变进行文献复习。
PKP1的Sanger测序鉴定出两个新的纯合移码突变：c.409_410insAC（p。thr137thrfs*61）和c.1213delA（p。Arg411Glufs*22）。对18例双等位基因PKP1基因突变的患者进行综合分析，但不是一个马赛克病例或6个缺乏基因突变研究的额外病例。所有致病性种系突变均为功能丧失（剪接位点，移码,无义）内含子1共有受体剪接位点的突变（c.203-1>A或G>T）代表复发性发现。所有受影响的个体都存在皮肤脆性和指甲受累(18/18)，大多数病例显示掌plant角化病（16/18），脱发/毛发减少（16/18）和口周裂痕/唇炎（12/15；3例未评论）。一些人的进一步观察包括瘙痒，未能在低身高/体重百分位数的情况下茁壮成长，毛囊角化过度,多汗症,行走困难,牙列发育不良和复发性胸部感染。
这些数据扩展了EDSF综合征的分子基础，并有助于定义这种桥粒遗传病的原型和可变表现。
