Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2.
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.
Aten
Emmelien
E
Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Nederlands. E.Aten@lumc.nl
Brasz
Lisa C
LC
Bornholdt
Dorothea
D
Hooijkaas
Ingeborg B
IB
Porteous
Mary E
ME
Sybert
Virginia P
VP
Vermeer
Maarten H
MH
Vossen
Rolf H A M
RH
van der Wielen
Michiel J R
MJ
Bakker
Egbert
E
Breuning
Martijn H
MH
Grzeschik
Karl-Heinz
KH
Oosterwijk
Jan C
JC
den Dunnen
Johan T
JT
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
D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human