IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.
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.
Department of Human Genetics, Philipps-Universität, Marburg 35037, Germany.
Frank
F
Oeffner
Gayle
G
Fischer
Rudolf
R
Happle
Arne
A
König
Regina C
RC
Betz
Dorothea
D
Bornholdt
Ulrike
U
Neidel
María del Carmen
Mdel C
Boente
Silke
S
Redler
Javier
J
Romero-Gomez
Aïcha
A
Salhi
Angel
A
Vera-Casaño
Christian
C
Weirich
Karl-Heinz
KH
Grzeschik
D000505:Alopecia / Q000151:congenital / Q000201:enzymology* / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005816:Genetic Complementation Test; D006706:Homeostasis; D006801:Humans; D016114:Ichthyosis, X-Linked / Q000201:enzymology* / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020795:Photophobia / Q000201:enzymology* / Q000235:genetics*; D013312:Stress, Physiological; D013577:Syndrome; D014162:Transfection
D002784:Cholesterol; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human