Nicastrin haploinsufficiency alters expression of type I interferon‐stimulated genes: the relationship to familial hidradenitis suppurativa
L Cao, DJ Morales‐Heil… - Clinical and experimental …, 2019 - academic.oup.com
L Cao, DJ Morales‐Heil, EDO Roberson
Clinical and experimental dermatology, 2019•academic.oup.comBackground Hidradenitis suppurativa (HS), also called acne inversa, is a chronic skin
disease. The symptoms can be severe, and include intensely painful nodules and
abscesses in apocrine‐gland rich inverse skin, such as the buttocks, under the arms and in
the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have
heterozygous loss‐of‐function rare variants in the γ‐secretase complex component nicastrin
(NCSTN). Aim To investigate the effect of NCSTN haploinsufficiency on human keratinocytes …
disease. The symptoms can be severe, and include intensely painful nodules and
abscesses in apocrine‐gland rich inverse skin, such as the buttocks, under the arms and in
the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have
heterozygous loss‐of‐function rare variants in the γ‐secretase complex component nicastrin
(NCSTN). Aim To investigate the effect of NCSTN haploinsufficiency on human keratinocytes …
Background
Hidradenitis suppurativa (HS), also called acne inversa, is a chronic skin disease. The symptoms can be severe, and include intensely painful nodules and abscesses in apocrine‐gland rich inverse skin, such as the buttocks, under the arms and in the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have heterozygous loss‐of‐function rare variants in the γ‐secretase complex component nicastrin (NCSTN).
Aim
To investigate the effect of NCSTN haploinsufficiency on human keratinocytes and assess potential mechanisms for lesion development.
Methods
NCSTN was knocked down using a small hairpin RNA construct in both a keratinocyte cell line (HEK001) and an embryonic kidney cell line (HEK293), and differential gene expression was assessed using RNA microarray. Using the HEK293 line, a heterozygous deletion of NCSTN was created with CRISPR/Cas9 genome editing, and nuclear factor kappa B activity was assessed using a luciferase reporter.
Results
Compared with controls, the keratinocyte NCSTN knockdown cell line showed a significantly increased expression of genes related to the type I interferon response pathway. Both HEK001 and HEK293 knockdowns demonstrated evidence of altered growth. There was a small but significant increase in nuclear factor kappa B signalling in response to tumour necrosis factor treatment in HEK293 cells genome‐edited for reduced NCSTN.
Conclusions
Our data suggest a role for increased keratinocyte inflammatory responsiveness in familial HS. Confirming this phenotype and characterizing additional effects in different cell types will require study beyond cell lines, such as in primary cells and tissues.
Oxford University Press