Rare catastrophes and evolutionary legacies: human germline gene variants in MLKL and the necroptosis signalling pathway.

Sarah E Garnish,Joanne M Hildebrand

doi:10.1042/bst20210517

Abstract

Programmed cell death has long been characterised as a key player in the development of human disease. Necroptosis is a lytic form of programmed cell death that is universally mediated by the effector protein mixed lineage kinase domain-like (MLKL), a pseudokinase. MLKL's activating kinase, receptor interacting protein kinase 3 (RIPK3), is itself activated within context specific scaffolds of receptor interacting protein kinase 1 (RIPK1), Z-DNA Binding Protein-1 (ZBP1) or TIR domain-containing adaptor inducing interferon-β (TRIF). These core necroptosis modulating proteins have been comprehensively revealed as potent drivers and suppressors of disease in inbred mouse strains. However, their roles in human disease within the ‘real world’ of diverse genetic backgrounds, natural infection and environmental challenges remains less well understood. Over 20 unique disease-associated human germline gene variants in this core necroptotic machinery have been reported in the literature and human clinico-genetics databases like ClinVar to date. In this review, we provide an overview of these human gene variants, with an emphasis on those encoding MLKL. These experiments of nature have the potential to not only enrich our understanding of the basic biology of necroptosis, but offer important population level insights into which clinical indications stand to benefit most from necroptosis-targeted drugs.

Highlights

Programmed cell death takes many forms and is crucial to every aspect of normal animal development and homeostasis
Based on observations of important mixed lineage kinase domain-like (MLKL) regulatory genes gleaned from genetically modified mice [20], we have plotted for the purposes of this review the number of disease associated human mutations reported in ClinVar [52], as accessed in September 2021 (Figure 2A)
The higher missense and loss of function (LOF) variation tolerance profiles of MLKL, receptor interacting protein kinase 3 (RIPK3) and Z-DNA Binding Protein-1 (ZBP1) indicate that gene variants are less likely to result in a loss of reproductive fitness that would cause them to be subject to purifying selection over time [55]

Summary

Introduction

Programmed cell death takes many forms and is crucial to every aspect of normal animal development and homeostasis. Only four individuals that are homozygous for a predicted loss of function (LOF) MLKL gene variant have been reported in the gnomAD database, a carefully curated collection of whole genome or exome data for over 140 000 human adults of diverse ancestry [21].

Results

Conclusion