TY - JOUR
T1 - Novel genotypes, phenotypes, and triggers in humans with OTULIN haploinsufficiency
AU - van der Linden, Tristan J
AU - Arts, Rob J W
AU - Biggs, Catherine M
AU - Habibi, Laleh
AU - Batlle-Masó, Laura
AU - van Laarhoven, Arjan
AU - Scheepmaker, Lisette M
AU - Yousefi, Pariya
AU - Gómez-Raccio, Andrea C
AU - Alizadeh, Zahra
AU - Mulders-Manders, Catharina M
AU - Oever, Jaap Ten
AU - Schuurs-Hoeijmakers, Janneke
AU - Alipour-Olyei, Nasrin
AU - Molitor, Anne
AU - Di Giovanni, Daniela
AU - Carapito, Raphael
AU - Bahram, Seiamak
AU - Seminario, Gisela
AU - Bezrodnik, Liliana
AU - Momenilandi, Mana
AU - Shahrooei, Mohammad
AU - Bustamante, Jacinta
AU - Aksentijevich, Ivona
AU - Kastner, Daniel
AU - Fazlollahi, Mohammad R
AU - Colobran, Roger
AU - Turvey, Stuart E
AU - van de Veerdonk, Frank L
AU - Casanova, Jean-Laurent
AU - Boisson, Bertrand
AU - Bardoel, Bart W
AU - Spaan, András N
N1 - Publisher Copyright:
© 2025 van der Linden et al.
PY - 2025/11/3
Y1 - 2025/11/3
N2 - Human OTULIN haploinsufficiency predisposes to life-threatening necrosis of the skin and lungs. Disease is triggered by infectious agents, typically Staphylococcus aureus, as well as unknown etiologies. We describe and characterize six unrelated patients who carry rare, predicted deleterious variants of OTULIN in heterozygosity. In addition to staphylococcal infections, the disease in the patients is elicited by previously underappreciated triggers, including mechanical or iatrogenic traumas and pseudomonal or clostridial infections. Severe necrosis of the lungs and/or skin are clinical hallmarks of their disease. By combining in vitro allele characterizations and functional studies in patients' cells, we demonstrate that the patients suffer from OTULIN haploinsufficiency. We provide guidance for assessing heterozygous OTULIN variants in diagnostic settings by evaluating in silico measures of predicted deleteriousness. The clinical course of the patients expands the genotypic and phenotypic spectrum of OTULIN haploinsufficiency and provides, in the light of a broadening of triggers, leads for therapeutic interventions.
AB - Human OTULIN haploinsufficiency predisposes to life-threatening necrosis of the skin and lungs. Disease is triggered by infectious agents, typically Staphylococcus aureus, as well as unknown etiologies. We describe and characterize six unrelated patients who carry rare, predicted deleterious variants of OTULIN in heterozygosity. In addition to staphylococcal infections, the disease in the patients is elicited by previously underappreciated triggers, including mechanical or iatrogenic traumas and pseudomonal or clostridial infections. Severe necrosis of the lungs and/or skin are clinical hallmarks of their disease. By combining in vitro allele characterizations and functional studies in patients' cells, we demonstrate that the patients suffer from OTULIN haploinsufficiency. We provide guidance for assessing heterozygous OTULIN variants in diagnostic settings by evaluating in silico measures of predicted deleteriousness. The clinical course of the patients expands the genotypic and phenotypic spectrum of OTULIN haploinsufficiency and provides, in the light of a broadening of triggers, leads for therapeutic interventions.
U2 - 10.70962/jhi.20250018
DO - 10.70962/jhi.20250018
M3 - Article
C2 - 41293556
SN - 3065-8993
VL - 1
JO - Journal of human immunity
JF - Journal of human immunity
IS - 4
M1 - e20250018
ER -