Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Dermatology and Allergology, Philipps-University Marburg, Marburg, Germany.
Br J Dermatol. 2023 Jan 23;188(1):94-99. doi: 10.1093/bjd/ljac019.
Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified.
We aimed to identify the genetic cause of HLP.
For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA -extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed -paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated.
In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46-62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients.
Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.
进行性指掌角皮症（HLP），亦称 Flegel 病，是一种罕见的皮肤疾病，表现为无症状的小角化过度丘疹。皮损常出现于足背部和小腿下部，通常在四十多岁后发病。HLP 疑似存在遗传基础；然而，迄今为止，尚未发现与 HLP 发病相关的基因缺陷。
确定 HLP 的遗传病因。
我们使用下一代测序（NGS）对 5 例 HLP 患者的队列进行了突变分析。我们使用了取自 2 例患者的新鲜皮肤活检样本和乙二胺四乙酸（EDTA）血样中的 DNA，以及 3 例患者的福尔马林固定石蜡包埋皮肤活检样本。此外，我们还研究了 4 例 HLP 皮损的免疫荧光染色。
通过 NGS，我们在 5 例 HLP 患者的所有样本中均发现了 SPTLC1 基因的罕见变异。在 4 例患者中我们检测到小的缺失/移码变异，在 1 例患者中检测到剪接变异，预计会干扰剪接过程。在血样中，检测到的变异为杂合子，等位基因频率分别为 49%和 50%。在皮肤活检中，等位基因频率在 46%-62%范围内。免疫荧光染色显示患者皮肤中的 SPTLC1 蛋白水平降低。
我们的研究结果提示 SPTLC1 基因的致病性变异是 HLP 的潜在遗传病因。值得注意的是，所鉴定的变异为移码或剪接变异，可能导致无意义介导的 mRNA 降解，从而导致 SPTLC1 蛋白水平降低。我们得出结论，鞘脂生物合成的关键酶 SPTLC1 减少导致 HLP 的发生，这突显了鞘脂途径作为一个新的治疗靶点。
