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Genotype–Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2
Author(s) -
Bornholdt Dorothea,
Atkinson T. Prescott,
Bouadjar Bakar,
Catteau Benoit,
Cox Helen,
Silva Deepthi,
Fischer Judith,
Gunasekera Chalukya N.,
HadjRabia Smaïl,
Happle Rudolf,
HolderEspinasse Muriel,
Kaminski Elke,
König Arne,
Mégarbané André,
Mégarbané Hala,
Neidel Ulrike,
Oeffner Frank,
Oji Vinzenz,
Theos Amy,
Traupe Heiko,
Vahlquist Anders,
Bon Bregje W.,
Virtanen Marie,
Grzeschik KarlHeinz
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22275
Subject(s) - missense mutation , biology , genetics , phenotype , ichthyosis vulgaris , gene , immunology , filaggrin , atopic dermatitis
Missense mutations affecting membrane‐bound transcription factor protease site 2 ( MBTPS 2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia ( IFAP ) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and O lmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS 1, 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.774 C > G (p. I 258 M ); c.758 G > C (p. G 253 A ); c.686 T > C (p. F 229 S ); c.1427 T > C (p. L 476 S ); c.1430 A > T (p. D 477 V ); c.1499 G > A (p. G 500 D ); c.1538 T > C (p. L 513 P )], four had previously been reported in unrelated sibships [c.261 G > A (p. M 87 I ); c.1286 G > A (p. R 429 H ); c.1424 T > C (p. F 475 S ); c.1523 A > G (p. N 508 S )]. 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 MBTPS 2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X ‐linked, O lmsted syndrome, or possibly further X ‐linked traits with an oculocutaneous component.