title: 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.
authors: Institut fuer Humangenetik, Philipps-Universitaet, Marburg, Germany.
authors: Dorothea
authors: D
authors: Bornholdt
authors: T Prescott
authors: TP
authors: Atkinson
authors: Bakar
authors: B
authors: Bouadjar
authors: Benoit
authors: B
authors: Catteau
authors: Helen
authors: H
authors: Cox
authors: Deepthi
authors: D
authors: De Silva
authors: Judith
authors: J
authors: Fischer
authors: Chalukya N
authors: CN
authors: Gunasekera
authors: Smaïl
authors: S
authors: Hadj-Rabia
authors: Rudolf
authors: R
authors: Happle
authors: Muriel
authors: M
authors: Holder-Espinasse
authors: Elke
authors: E
authors: Kaminski
authors: Arne
authors: A
authors: König
authors: André
authors: A
authors: Mégarbané
authors: Hala
authors: H
authors: Mégarbané
authors: Ulrike
authors: U
authors: Neidel
authors: Frank
authors: F
authors: Oeffner
authors: Vinzenz
authors: V
authors: Oji
authors: Amy
authors: A
authors: Theos
authors: Heiko
authors: H
authors: Traupe
authors: Anders
authors: A
authors: Vahlquist
authors: Bregje W
authors: BW
authors: van Bon
authors: Marie
authors: M
authors: Virtanen
authors: Karl-Heinz
authors: KH
authors: Grzeschik
mesh_terms: D000293:Adolescent; D000483:Alleles; D000505:Alopecia / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D005816:Genetic Complementation Test; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007057:Ichthyosis / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D010641:Phenotype; D020795:Photophobia / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D012873:Skin Diseases, Genetic / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
chemical_list: D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human