A homozygous p.Leu813Pro gain-of-function NLRP1 variant causes phenotypes of different severity in two siblings

Background: A trio exome sequencing study identified a previously unreported NLRP1 gene variant resulting in a p.Leu813Pro substitution of the LRR (leucine-rich repeats) domain of the NLRP1 protein (NACHT, LRR and PYD domains-containing protein 1). This homozygous mutation was shared by two sisters with different clinical presentation: the younger sister had generalized inflammatory nodules with keratotic plugs, clinically resembling multiple keratoacanthomas, while the older had manifestations of familial keratosis lichenoides chronica. Objectives: To analyse the consequences of this NLRP1 variant in two siblings with a different clinical spectrum of severity. Methods: To demonstrate the pathogenicity, p.Leu813Pro was recombinantly expressed, and its effect on inflammasome assembly was assessed. Exome sequencing and RNA-Seq were performed to identify factors with potentially modifying effects on the severity of the skin manifestation between each sibling. Results: The variant p.Leu813Pro triggered activation of the NLRP1 inflammasome leading to ASC (apoptosis-associated speck-like protein containing a CARD) speck formation and interleukin (IL)-1β release. The more severely affected sister had several additional genomic variants associated with atopy and psoriasis that were not present in her sibling. IL-5 and IL-17 emerged as dominant cytokines driving prominent inflammation in the skin of the severely affected sibling. Conclusions: To the best of our knowledge, this is the first report of a NLRP1 variant that leads to a different clinical spectrum of severity within the same sibship. IL-5 and IL-17 were the main cytokines expressed in the inflammatory lesions of the severely affected patient and might be regarded as disease modifying factors, and therefore may be considered as therapeutic targets.