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Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2
Author(s) -
Aten Emmelien,
Brasz Lisa C.,
Bornholdt Dorothea,
Hooijkaas Ingeborg B.,
Porteous Mary E.,
Sybert Virginia P.,
Vermeer Maarten H.,
Vossen Rolf H.A.M.,
van der Wielen Michiel J.R.,
Bakker Egbert,
Breuning Martijn H.,
Grzeschik KarlHeinz,
Oosterwijk Jan C.,
den Dunnen Johan T.
Publication year - 2010
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.21335
Subject(s) - missense mutation , biology , genetics , locus (genetics) , phenotype , candidate gene , allele , palmoplantar keratoderma , genetic heterogeneity , gene
Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9‐Mb region at Xp22.12–Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X‐linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X‐inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element‐binding proteins (SREBPs). In vitro functional expression studies of the c.1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype. Hum Mutat 31:1–9, 2010. © 2010 Wiley‐Liss, Inc.