Biology subjects

Zahra, D.

Publications and source records attributed to Zahra, D..

3 recordsLinked to original sources

bioRxiv2022

Environmental and genetic disease modifiers of haploinsuffciency of A20

Monogenic diseases can often manifest diverse clinical phenotypes and cause diagnostic dilemmas. While monoallelic loss-of-function variants in TNFAIP3 (Haploinsufficiency of A20; HA20) cause a highly penetrant autoinflammatory disease, the variable expressivity suggest a role for additional genetic and environmental disease modifiers. Here, we identify critically ill children who inherited a family-specific TNFAIP3 deletion from one of their otherwise healthy parents. Each of the probands also inherited in trans a subtle loss-of-function I207L TNFAIP3 variant that is common in Oceania, originally introgressed from Denisovans. Modelling this compound heterozgous state in mice under specific pathogen free conditions demonstrated a reduced threshold to break immune tolerance. Exaggerated immune responses were precipitated by inheriting the two genetic hits on the TNFAIP3 checkpoint coupled with increasing the microbial challenge to immune tolerance, either by co-housing with pet store mice carrying a wild microbial burden or by transient dietary exposure to a chemical that diminishes the intestinal mucin barrier separating gut microbes from immune sensing systems. These data illuminate second-hit genetic and environmental modifiers contributing to complex inflammatory and autoimmune disease. Increased mechanistic understanding of the presence and contribution of disease modifiers will aid diagnostic and prognostic patient stratification and potentially reveal novel therapeutic opportunities.

immunology↗

bioRxiv2022

Increased core body temperature exacerbates defective protein prenylation in mouse avatars of mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is caused by biallelic loss-of-function mutations in MVK, leading to recurrent fevers and systemic inflammation. We describe new mouse avatars of MKD bearing p.Val377Ile (the commonest variant) or deletions in Mvk. Compound heterozygous mice recapitulated the biochemical phenotype of MKD, with build-up of unprenylated GTPases and increased plasma mevalonic acid. Mice with different deficiencies in mevalonate kinase revealed new insights into the genotype-phenotype relationship and mirrored the variability in the prenylation defect in human MKD, with p.V377I homozygous mice having a milder phenotype than compound heterozygous animals. The inflammatory response to LPS was enhanced in compound heterozygous mice in vivo and elevated serum interleukin-1{beta} was abrogated by NLRP3 inflammasome inhibition. Increased temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares and an additional potential target for future therapeutic approaches.

physiology↗

bioRxiv2019

Phospho-tuning immunity through Denisovan, modern human, and mouse TNFAIP3 gene variants

Resisting or tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here, genomic analyses of anatomically modern humans, extinct Denisovan hominins, and mice revealed a series of missense variants in the immune response inhibitor A20 (encoded by TNFAIP3), substituting non-catalytic residues of the ubiquitin protease domain to diminish I{kappa}B-dependent phosphorylation and activation of A20. Two A20 variants with partial phosphorylation deficits appeared beneficial: one originating in Denisovans and introgressed in modern humans throughout Oceania, and another in a mouse strain resistant to Coxsackievirus. By contrast, a variant with 95% loss of phosphorylation caused spontaneous inflammatory disease in humans and mice. Analysis of the partial phosphorylation variant in mice revealed diminished tolerance of bacterial lipopolysaccharide or to poxvirus inoculation as trade-offs for enhanced immunity.\n\nOne Sentence SummaryModern and ancient variants reveal a genetically tunable element for balancing immunity and microbial tolerance.

immunology↗