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.

journal_name

Exp Dermatol

journal_title

Experimental dermatology

authors

Oeffner F,Martinez F,Schaffer J,Salhi A,Monfort S,Oltra S,Neidel U,Bornholdt D,van Bon B,König A,Happle R,Grzeschik KH

doi

10.1111/j.1600-0625.2010.01238.x

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

447-9

issue

5

eissn

0906-6705

issn

1600-0625

journal_volume

20

pub_type

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