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A homozygous p.Leu813Pro gain-of-function NLRP1 variant causes phenotypes of different severity in two siblings.
Li, Mingfeng; Lay, Kenneth; Zimmer, Andreas; Technau-Hafsi, Kristin; Wong, Jasmine; Reimer-Taschenbrecker, Antonia; Rohr, Jan; Abdalla, Ebtesam; Fischer, Judith; Reversade, Bruno; Has, Cristina.
Afiliación
  • Li M; Department of Dermatology.
  • Lay K; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
  • Zimmer A; Institute of Human Genetics.
  • Technau-Hafsi K; Department of Dermatology.
  • Wong J; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
  • Reimer-Taschenbrecker A; Department of Dermatology.
  • Rohr J; Department of Paediatrics, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • Abdalla E; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
  • Fischer J; Institute of Human Genetics.
  • Reversade B; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore.
  • Has C; Department of Dermatology.
Br J Dermatol ; 188(2): 259-267, 2023 02 10.
Article en En | MEDLINE | ID: mdl-36763876
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)-1ß 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Reguladoras de la Apoptosis / Inflamasomas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Female / Humans Idioma: En Revista: Br J Dermatol Año: 2023 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Reguladoras de la Apoptosis / Inflamasomas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Female / Humans Idioma: En Revista: Br J Dermatol Año: 2023 Tipo del documento: Article