IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

IFAP综合征是一种罕见的遗传性疾病，其特征是卵泡鱼鳞病，Atrichia和畏光。先前的研究发现，MBTPS2的编码位点2-蛋白酶（S2P）的突变是X连锁IFAP综合征的基础。本报告介绍了通过全外显子组测序对11名不相关，种族不同的具有常染色体显性IFAP综合征的个体进行SREBF1中三个杂合突变的鉴定。SREBF1编码固醇调节元件结合蛋白1（SREBP1），它促进参与脂肪酸和胆固醇生物合成的脂基因的转录。此过程需要通过位点1-蛋白酶（S1P）和S2P切割SREBP1，然后将其转位到与固醇调节元件（SRE）结合的核中。检测到的三个SREBF1突变导致取代或缺失残基527、528和530，这对于S1P裂解至关重要。体外对SREBP1变体的研究表明S1P裂解受损，从而阻止了SREBP1转录活性形式的核易位。结果，如荧光素酶报告基因检测所证实，与野生型相比，SREBP1变体表现出明显更低的转录活性。来自受IFAP影响的个体的头皮皮肤的RNA测序显示，低密度脂蛋白受体（LDLR）和已知在毛囊外根鞘中表达的角蛋白基因的转录水平显着降低。原位速率增加在受影响患者的头皮样本中也检测到了角质形成细胞凋亡，这可能导致皮肤过度角化和hypertrichosis。与以前的研究一起，本研究结果表明，SREBP信号传导在表皮分化，皮肤屏障形成，头发生长和眼睛功能中起重要作用。