Additional Supporting Information may be found in the online version of this article.
Genotype–Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2
Article first published online: 8 MAR 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 4, pages 587–594, April 2013
How to Cite
Bornholdt, D., Atkinson, T. P., Bouadjar, B., Catteau, B., Cox, H., De Silva, D., Fischer, J., Gunasekera, C. N., Hadj-Rabia, S., Happle, R., Holder-Espinasse, M., Kaminski, E., König, A., Mégarbané, A., Mégarbané, H., Neidel, U., Oeffner, F., Oji, V., Theos, A., Traupe, H., Vahlquist, A., van Bon, B. W., Virtanen, M. and Grzeschik, K.-H. (2013), Genotype–Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2. Hum. Mutat., 34: 587–594. doi: 10.1002/humu.22275
Communicated by Andrew Wilkie
Contract grant sponsor: BMBF (Netzwerk für Ichthyosen und verwandte Verhornungsstörungen, NIRK).
- Issue published online: 20 MAR 2013
- Article first published online: 8 MAR 2013
- Accepted manuscript online: 12 JAN 2013 10:26PM EST
- Manuscript Accepted: 20 DEC 2012
- Manuscript Received: 21 SEP 2012
- BMBF (Netzwerk für Ichthyosen und verwandte Verhornungsstörungen, NIRK)
- IFAP syndrome;
Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype–phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.