Wang, Huijun, Humbatova, Aytaj, Liu, Yuanxiang, Qin, Wen, Lee, Mingyang, Cesarato, Nicole, Kortuem, Fanny, Kumar, Sheetal, Romano, Maria Teresa, Dai, Shangzhi, Mo, Ran, Sivalingam, Sugirthan, Motameny, Susanne, Wu, Yuan, Wang, Xiaopeng, Niu, Xinwu, Geng, Songmei, Bornholdt, Dorothea, Kroisel, Peter M., Tadini, Gianluca, Walter, Scott D., Hauck, Fabian, Girisha, Katta M., Calza, Anne-Marie, Bottani, Armand, Altmueller, Janine, Buness, Andreas, Yang, Shuxia, Sun, Xiujuan, Ma, Lin, Kutsche, Kerstin, Grzeschik, Karl-Heinz, Betz, Regina C. and Lin, Zhimiao (2020). Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome. Am. J. Hum. Genet., 107 (1). S. 34 - 46. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wang, HuijunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Humbatova, AytajUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, YuanxiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Qin, WenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, MingyangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cesarato, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kortuem, FannyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumar, SheetalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romano, Maria TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dai, ShangzhiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mo, RanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sivalingam, SugirthanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XiaopengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niu, XinwuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geng, SongmeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bornholdt, DorotheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroisel, Peter M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tadini, GianlucaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walter, Scott D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauck, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Girisha, Katta M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Calza, Anne-MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bottani, ArmandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buness, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, ShuxiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, XiujuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, LinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutsche, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grzeschik, Karl-HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Betz, Regina C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, ZhimiaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-327047
DOI: 10.1016/j.ajhg.2020.05.006
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 107
Number: 1
Page Range: S. 34 - 46
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ICHTHYOSIS-FOLLICULARIS; CHOLESTEROL HOMEOSTASIS; HAIR; PHOTOPHOBIA; PROTEIN; DEFICIENCY; EXPRESSION; ALOPECIA; CLEAVAGE; ATRICHIAMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32704

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