Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations inMBTPS2

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.

Expanding the phenotype of IFAP/BRESECK syndrome: A new case with severe hypogammaglobulinemia

“…This case presents with overlapping features of several patients previously reported with the diagnosis of IFAP or BRESHECK syndrome before the lumping of these syndromes within the same entity [6,7].…”

“…The fourth report was a 4 years-old Japanese male patient with BRESHECK syndrome [7]. The last reported patient was a French male with IFAP syndrome [6]. The clinical features of IFAP/BRESHECK syndrome cases with p.R429H mutation in MBTPS2 are summarized in Table 1.…”

“…In all of this four patients molecular studies of the MBTPS2 gene were not available. Recently a patient with the p.I258.M mutation was described with mild B cell lymphopenia and poor antibody response [6]. Other authors have reported atopic features like urticaria, atopic dermatitis, cow's milk protein allergy and anaphylaxis [3,4,11,16].…”

“…IFAP/BRESHECK syndrome is caused by MBTPS2 missense and intronic mutations [3,5,6,17]. These mutations have a significant variation in residual activity, so that the mutants with the lowest residual activity are associated to the most severe clinical phenotypes.…”

“…These mutations have a significant variation in residual activity, so that the mutants with the lowest residual activity are associated to the most severe clinical phenotypes. The mutation p.R429H is the most severe variant with the lowest residual activity [3,6,7].…”