Whole Genome Linkage Analysis Followed by Whole Exome Sequencing Identifies Nicastrin (NCSTN) as a Causative Gene in a Multiplex Family with γ-Secretase Spectrum of Autoinflammatory Skin Phenotypes

Abstract

significant repigmentation in vitiligo was reported with tofacitinib citrate treatment (Craiglow et al., 2015). A case of reversal of alopecia areata has been observed with baricitinib treatment (Jabbari et al., 2015). In summary, we demonstrate a substantial benefit from ruxolitinib therapy in a case of chilblain LE. Our observation supports the idea that JAK/STAT inhibition provides a promising therapeutic approach for the treatment of cutaneous autoimmune diseases, particularly LE. CONFLICT OF INTEREST DW reports research support and honorary payments from Novartis. JW, NvH, JM, MV, and TB state no conflicts of interest.

A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

“…Dear Editor , NCSTN encodes nicastrin, one of the three subunits of γ‐secretase, a transmembrane endoprotease complex that catalyses the cleavage of many transmembrane proteins including Notch receptors . In 2010, mutations in genes encoding γ‐secretase subunits ( NCSTN , PSENEN and PSEN1 ) were reported in patients with hidradenitis suppurativa (HS) .…”

“…In 2010, mutations in genes encoding γ‐secretase subunits ( NCSTN , PSENEN and PSEN1 ) were reported in patients with hidradenitis suppurativa (HS) . Elevated tumour necrosis factor‐α and interleukin (IL)‐10 levels in patients with HS with NCSTN mutations have been found, although other reports found no elevation or found decreases …”

PASH syndrome (pyoderma gangrenosum, acne and hidradenitis suppurativa): a disease with genetic heterogeneity

“…Investigations in 19 unrelated patients with PASH excluded mutations in the coding sequence of PSTPIP1 in all patients except three . Interestingly, a missense mutation within PSTPIP1 , previously reported in a patient with an aggressive form of PG, was identified in a patient with PASH syndrome .…”

“…Increased repetition of the CCTG microsatellite motif (more than five repeats) in the promoter region was initially reported on one allele in two patients with PASH . However, no increase in repeats of the microsatellite motif was noted in one case of PASH or in the patients in the Iranian family …”

“…Loss‐of‐function mutations in the γ‐secretase genes, nicastrin ( NCSTN ), presenilin enhancer‐2 ( PSENEN ) and presenilin‐1 ( PSEN1 ), have been reported in a small proportion of patients with HS . Recently, loss‐of‐function mutations in the NCSTN gene were identified in one of three unrelated patients with PASH and in an Iranian multiplex family …”