title: Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2.
abstract: 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.
authors.affiliation: Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Nederlands. E.Aten@lumc.nl
authors.forename: Emmelien
authors.initials: E
authors.lastname: Aten
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Brasz
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bornholdt
authors.forename: Ingeborg B
authors.initials: IB
authors.lastname: Hooijkaas
authors.forename: Mary E
authors.initials: ME
authors.lastname: Porteous
authors.forename: Virginia P
authors.initials: VP
authors.lastname: Sybert
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Vermeer
authors.forename: Rolf H A M
authors.initials: RH
authors.lastname: Vossen
authors.forename: Michiel J R
authors.initials: MJ
authors.lastname: van der Wielen
authors.forename: Egbert
authors.initials: E
authors.lastname: Bakker
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Grzeschik
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics; D007644:Darier Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D020125:Mutation, Missense; D009426:Netherlands; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human