| IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. | |
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MedLine Citation:
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PMID: 19361614 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Frank Oeffner; Gayle Fischer; Rudolf Happle; Arne König; Regina C Betz; Dorothea Bornholdt; Ulrike Neidel; María del Carmen Boente; Silke Redler; Javier Romero-Gomez; Aïcha Salhi; Angel Vera-Casaño; Christian Weirich; Karl-Heinz Grzeschik |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: American journal of human genetics Volume: 84 ISSN: 1537-6605 ISO Abbreviation: Am. J. Hum. Genet. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-13 Completed Date: 2009-04-24 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370475 Medline TA: Am J Hum Genet Country: United States |
Other Details:
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Languages: eng Pagination: 459-67 Citation Subset: IM |
Affiliation:
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Department of Human Genetics, Philipps-Universität, Marburg 35037, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alopecia
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congenital,
enzymology*,
genetics* Amino Acid Substitution Animals CHO Cells Case-Control Studies Cholesterol / metabolism Chromosomes, Human, X / genetics Cricetinae Cricetulus Endoplasmic Reticulum / metabolism Female Genetic Complementation Test Homeostasis Humans Ichthyosis, X-Linked / enzymology*, genetics* Infant, Newborn Male Metalloendopeptidases / deficiency*, genetics* Mutation, Missense Pedigree Phenotype Photophobia / enzymology*, genetics* Stress, Physiological Syndrome Transfection |
| Chemical | |
Reg. No./Substance:
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57-88-5/Cholesterol; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.85/MBTPS2 protein, human |
| Comments/Corrections | |
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