title: Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome.
abstract: Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome is an X-linked genodermatosis with congenital atrichia being the most prominent feature. Recently, we have shown that functional deficiency of MBTPS2 (membrane-bound transcription factor protease site 2) - a zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response - causes the disease. Here, we present results obtained by analysing two intronic MBTPS2 mutations, c.671-9T>G and c.225-6T>A, using in silico and cell-based splicing assays. Accordingly, the c.225-6T>A transversion generated a new splice acceptor site, which caused extension of exon 3 by four bases and subsequently introduced a premature stop codon. Both, minigene experiments and RT-PCR analysis with patient-derived mRNA, demonstrated that the c.671-9T>G mutation resulted in skipping of exon 6, most likely because of disruption of the polypyrimidin tract or a putative intronic splicing enhancer (ISE). Our combined biocomputational and experimental analysis strongly suggested that both intronic alterations are disease-causing mutations.
authors.forename: Frank
authors.initials: F
authors.lastname: Oeffner
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez
authors.forename: Julie
authors.initials: J
authors.lastname: Schaffer
authors.forename: Aïcha
authors.initials: A
authors.lastname: Salhi
authors.forename: Sandra
authors.initials: S
authors.lastname: Monfort
authors.forename: Silvestre
authors.initials: S
authors.lastname: Oltra
authors.forename: Ulrike
authors.initials: U
authors.lastname: Neidel
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bornholdt
authors.forename: Bregje
authors.initials: B
authors.lastname: van Bon
authors.forename: Arne
authors.initials: A
authors.lastname: König
authors.forename: Rudolf
authors.initials: R
authors.lastname: Happle
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Grzeschik
mesh_terms: D000328:Adult; D000465:Algorithms; D000505:Alopecia / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D019295:Computational Biology / Q000379:methods; D006801:Humans; D007057:Ichthyosis / Q000235:genetics*; D007438:Introns / Q000235:genetics*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D020795:Photophobia / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012984:Software
chemical_list: D022821:RNA Splice Sites; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human