2. Academic Validation
  3. Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome

  • Am J Hum Genet. 2020 Jul 2;107(1):34-45. doi: 10.1016/j.ajhg.2020.05.006.
Huijun Wang 1,  Aytaj Humbatova 2,  Yuanxiang Liu 3,  Wen Qin 1,  Mingyang Lee 1,  Nicole Cesarato 2,  Fanny Kortüm 4,  Sheetal Kumar 2,  Maria Teresa Romano 2,  Shangzhi Dai 1,  Ran Mo 1,  Sugirthan Sivalingam 5,  Susanne Motameny 6,  Yuan Wu 7,  Xiaopeng Wang 8,  Xinwu Niu 8,  Songmei Geng 8,  Dorothea Bornholdt 9,  Peter M Kroisel 10,  Gianluca Tadini 11,  Scott D Walter 12,  Fabian Hauck 13,  Katta M Girisha 14,  Anne-Marie Calza 15,  Armand Bottani 16,  Janine Altmüller 6,  Andreas Buness 5,  Shuxia Yang 1,  Xiujuan Sun 3,  Lin Ma 3,  Kerstin Kutsche 4,  Karl-Heinz Grzeschik 9,  Regina C Betz 17,  Zhimiao Lin 18
Affiliations

Affiliations

  • 1 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China.
  • 2 Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, 53127 Bonn, Germany.
  • 3 Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
  • 4 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 5 Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Medical Faculty, 53127 Bonn, Germany; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty, 53127 Bonn, Germany.
  • 6 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
  • 7 Department of Ophthalmology, Peking University First Hospital, Beijing 100034, China.
  • 8 Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
  • 9 Centre for Human Genetics, University of Marburg, 35033 Marburg, Germany.
  • 10 Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria.
  • 11 Pediatric Dermatology Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
  • 12 Retina Consultants, P.C., 43 Woodland Street, Suite 100, Hartford, CT 06105, USA.
  • 13 Department of Pediatrics, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 14 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India.
  • 15 Department of Dermatology and Venereology, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • 16 Service of Genetic Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • 17 Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, 53127 Bonn, Germany. Electronic address: [email protected].
  • 18 Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing 100034, China. Electronic address: [email protected].
PMID: 32497488 DOI: 10.1016/j.ajhg.2020.05.006
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.

Keywords

MBTPS2; SREBF1; atrichia; ichthyosis follicularis; photophobia; sterol biosynthesis.

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