A novel splice site mutation inNCSTNunderlies a Japanese family with hidradenitis suppurativa

Abstract

A novel splice site mutation, c.582+1delG, in NCSTN was identified in the familial patients with HS. We also reveal for the first time that a γ-secretase gene mutation is not linked to the development of nonfamilial HS. These results would further pave the way to a better understanding of the contribution of γ-secretase and other genes to the pathogenesis of HS and to the development of a new therapeutic strategy for HS.

Hidradenitis suppurativa: haploinsufficiency of gamma-secretase components does not affect gamma-secretase enzyme activityin vitro

“…These data demonstrate that the gamma‐secretase components nicastrin and PEN‐2 are expressed in cutaneous structures that are commonly distorted or altered in HS . The two mutations studied share a downstream pathogenic mechanism of haploinsufficiency (consistent with other globally reported gamma‐secretase gene mutations reportedly reducing transcript abundance) . However, the subsequent total cell reduction in respective protein expression was not replicated in cell membrane preparations.…”

“…7,8 The two mutations studied share a downstream pathogenic mechanism of haploinsufficiency (consistent with other globally reported gamma-secretase gene mutations reportedly reducing transcript abundance). [9][10][11] However, the subsequent total cell reduction in respective protein expression was not replicated in cell membrane preparations. Gamma-secretase protein expression is very tightly regulated; 12 < 5% of assembled complexes reach the cell membrane.…”

Genetic analysis of NCSTN for potential association with hidradenitis suppurativa in familial and nonfamilial patients

“…To find genetic variants that are associated with HS susceptibility, research has focused on sequencing the three essential subunits of γ‐secretase in kindreds of patients with HS . To date, 20 mutations in nicastrin (NCSTN) have been reported in African American, Chinese, Japanese, South Welsh and French multiplex kindreds, with NCSTN being the most commonly observed subunit . Mutations in NCSTN include four deletions (c.210_211delAG, c.487delC, c.1752delG and c.582+1delG) that result in a frame shift.…”

“…3 To date, 20 mutations in nicastrin (NCSTN) have been reported in African American, Chinese, Japanese, South Welsh and French multiplex kindreds, with NCSTN being the most commonly observed subunit. [4][5][6][7][8] Mutations in NCSTN include four deletions (c.210_211delAG, c.487delC, c.1752delG and c.582+1delG) that result in a frame shift. In addition, 10 nonsense mutations that prematurely stop the translation of the mRNA sequence and induce loss of function (p.R117X, p.R434X, p.Y565X, p.S590AfsX3, p.V75I, p.D185N, p.P211R, p.Q216P, p.Q568X and p.Q420X) have been identified, which could potentially disrupt the structure of NCSTN, leading to impaired activity.…”

Acne and hidradenitis suppurativa

“…66 Mutations have since been reported in two British, six Chinese, one Japanese and three French multiplex kindreds, as well as four apparently sporadic cases. [68][69][70][71][72][73][74] To date, eighteen mutations have been reported in NCSTN, three in PSE-NEN and one in PSEN1, 67,[70][71][72][73]75 of which four are nonsense mutations, seven result in frameshifts, seven result in altered splicing and four are missense mutations.…”