背景:MaldeMeleda是一种常染色体隐性遗传的掌足底角化病,SLURP1被鉴定为致病基因。尽管已经报道了超过20个SLURP1突变,只有突变c.256G>A(p.G87R)已在中国患者中检测到。这里,我们报道了一个中国家庭中的一个新的杂合SLURP1突变。
方法:我们评估了两名中国MaldeMeleda患者的临床表现,并从患者和其他家庭成员收集标本进行全外显子组和Sanger测序。我们使用了算法(MutationTaster,SIFT,PolyPhen-2,PROVEAN,PANTHER,FATHMM,mCSM,SDM和DUET)来预测检测到的突变的致病潜力。我们还使用AlphaFold2和PyMOL进行蛋白质结构分析。
结果:2例患者均表现为掌趾角化病的典型表现。在Proband1中,我们在SLURP1的外显子3中检测到了一个新的复合杂合突变(c.243C>A和c.256G>A)。Proband2是一个近亲家族的成年女性,具有纯合突变(c.211C>T)。算法表明这两种突变可能是致病的。我们使用AlphaFold2来预测这些突变的蛋白质结构,发现它们会导致不稳定,如PyMOL所示。
结论:我们的研究在中国MaldeMeleda患者中发现了一种新的复合杂合突变(c.243C>A和c.256G>A),该突变可能导致蛋白质结构不稳定。此外,本研究扩展了SLURP1突变的现有知识,有助于了解MaldeMeleda.
Mal de Meleda is an autosomal recessive palmoplantar keratoderma, with SLURP1 identified as the pathogenic gene responsible. Although over 20 mutations in SLURP1 have been reported, only the mutation c.256G > A (p.G87R) has been detected in Chinese patients. Here, we report a novel heterozygous SLURP1 mutation in a Chinese family.
We assessed the clinical manifestations of two Chinese patients with Mal de Meleda and collected specimens from the patients and other family members for whole-exome and Sanger sequencing. We used algorithms (MutationTaster, SIFT, PolyPhen-2, PROVEAN, PANTHER, FATHMM, mCSM, SDM and DUET) to predict the pathogenetic potential of the mutation detected. We also employed AlphaFold2 and PyMOL for protein structure analysis.
Both patients displayed the typical manifestation of palmoplantar keratoderma. In Proband 1, we detected a novel compound heterozygous mutation (c.243C > A and c.256G > A) in exon 3 of SLURP1. Proband 2 was an adult female born to a consanguineous family and carried a homozygous mutation (c.211C > T). Algorithms indicated both mutations to be probably disease causing. We used AlphaFold2 to predict the protein structure of these mutations and found that they cause instability, as shown by PyMOL.
Our study identified a novel compound heterozygous mutation (c.243C > A and c.256G > A) in a Chinese patient with Mal de Meleda that has the potential to cause instability in protein structure. Moreover, this study expands on the existing knowledge of SLURP1 mutations and contributes to knowledge of Mal de Meleda.