Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2
Résumé
Keratosis Follicularis Spinulosa Decalvans, (KFSD, OMIM 308800) 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 chal-lenging. Towards identification of the causative gene we re-analysed a large Dutch KFSD family. 1M SNP arrays 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 iden-tified in two unrelated X-linked KFSD families and cosegregated with KFSD in all fami-lies. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regula-tory element-binding proteins (SREBPs). In vitro functional expression studies of the c.1523A>G mutation showed that sterol responsiveness was reduced by half. Other mis-sense mutations in MBTPS2 have recently been identified in patients with IFAP syn-drome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype.
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