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Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.

Abstract
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.
AuthorsDorothea Bornholdt, T Prescott Atkinson, Bakar Bouadjar, Benoit Catteau, Helen Cox, Deepthi De Silva, Judith Fischer, Chalukya N Gunasekera, Smaïl Hadj-Rabia, Rudolf Happle, Muriel Holder-Espinasse, Elke Kaminski, Arne König, André Mégarbané, Hala Mégarbané, Ulrike Neidel, Frank Oeffner, Vinzenz Oji, Amy Theos, Heiko Traupe, Anders Vahlquist, Bregje W van Bon, Marie Virtanen, Karl-Heinz Grzeschik
JournalHuman mutation (Hum Mutat) Vol. 34 Issue 4 Pg. 587-94 (Apr 2013) ISSN: 1098-1004 [Electronic] United States
PMID23316014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 Wiley Periodicals, Inc.
Chemical References
  • Metalloendopeptidases
  • MBTPS2 protein, human
Topics
  • Adolescent
  • Alleles
  • Alopecia (diagnosis, genetics)
  • Animals
  • Cell Line
  • Child
  • Child, Preschool
  • Female
  • Genetic Association Studies
  • Genetic Complementation Test
  • Genetic Diseases, X-Linked (diagnosis, genetics)
  • Humans
  • Ichthyosis (diagnosis, genetics)
  • Male
  • Metalloendopeptidases (chemistry, genetics, metabolism)
  • Microsatellite Repeats
  • Mutation, Missense
  • Phenotype
  • Photophobia (diagnosis, genetics)
  • Polymorphism, Single Nucleotide
  • Protein Transport
  • Skin Diseases, Genetic (diagnosis, genetics)
  • Young Adult

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