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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
IFAP Syndrome Is Caused by Deficiency in MBTPS2, an Intramembrane Zinc Metalloprotease Essential for Cholesterol Homeostasis and ER Stress Response
American Journal of Human Genetics, Volume 84, No. 4, Year 2009
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Description
Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype. MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in sterol control of transcription and ER stress response. Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids. These functions were impaired in five mutations as detected in unrelated patients. The degree of diminished activity correlated with clinical severity as noted in male patients. Our findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress. © 2009 The American Society of Human Genetics.
Authors & Co-Authors
Oeffner, Frank
Germany, Marburg
Philipps-universität Marburg
Fischer, Gayle
Australia, Sydney
The University of Sydney Northern Clinical School
Happle, Rudolph
Germany, Marburg
Philipps-universität Marburg
König, Arne
Germany, Marburg
Philipps-universität Marburg
Betz, Regina Christine
Germany, Bonn
Universität Bonn
Bornholdt, Dorothea
Germany, Marburg
Philipps-universität Marburg
Neidel, Ulrike
Germany, Marburg
Philipps-universität Marburg
del Carmen Boente, María
Argentina, San Miguel de Tucuman
Hospital Del Niño Jesus, Argentina
Redler, Silke
Germany, Bonn
Universität Bonn
Romero-Gomez, Javier
Unknown Affiliation
Salhi, Aïcha
Algeria, Algiers
Université D’alger 1
Vera-Casaño, Ángel
Spain, Malaga
Hospital Regional Universitario Carlos Haya
Weirich, Christian
Germany, Marburg
Philipps-universität Marburg
Grzeschik, Karl Heinz
Germany, Marburg
Philipps-universität Marburg
Statistics
Citations: 130
Authors: 14
Affiliations: 6
Identifiers
Doi:
10.1016/j.ajhg.2009.03.014
ISSN:
00029297
Research Areas
Genetics And Genomics
Participants Gender
Male