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A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

ABSTRACT: MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl^D139V, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl^D139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).

SUBMITTER: Hildebrand JM

PROVIDER: S-EPMC7305203 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

Hildebrand Joanne M JM Kauppi Maria M Majewski Ian J IJ Liu Zikou Z Cox Allison J AJ Miyake Sanae S Petrie Emma J EJ Silk Michael A MA Li Zhixiu Z Tanzer Maria C MC Brumatti Gabriela G Young Samuel N SN Hall Cathrine C Garnish Sarah E SE Corbin Jason J Stutz Michael D MD Di Rago Ladina L Gangatirkar Pradnya P Josefsson Emma C EC Rigbye Kristin K Anderton Holly H Rickard James A JA Tripaydonis Anne A Sheridan Julie J Scerri Thomas S TS Jackson Victoria E VE Czabotar Peter E PE Zhang Jian-Guo JG Varghese Leila L Allison Cody C CC Pellegrini Marc M Tannahill Gillian M GM Hatchell Esme C EC Willson Tracy A TA Stockwell Dina D de Graaf Carolyn A CA Collinge Janelle J Hilton Adrienne A Silke Natasha N Spall Sukhdeep K SK Chau Diep D Athanasopoulos Vicki V Metcalf Donald D Laxer Ronald M RM Bassuk Alexander G AG Darbro Benjamin W BW Fiatarone Singh Maria A MA Vlahovich Nicole N Hughes David D Kozlovskaia Maria M Ascher David B DB Warnatz Klaus K Venhoff Nils N Thiel Jens J Biben Christine C Blum Stefan S Reveille John J Hildebrand Michael S MS Vinuesa Carola G CG McCombe Pamela P Brown Matthew A MA Kile Benjamin T BT McLean Catriona C Bahlo Melanie M Masters Seth L SL Nakano Hiroyasu H Ferguson Polly J PJ Murphy James M JM Alexander Warren S WS Silke John J

Nature communications 20200619 1

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl<sup>D139V</sup>, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl< ...[more]

PMID: 32561755

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Project description:Hypophosphatasia (HP) is a rare genetic disease caused by mutation in the alkaline phosphatase, liver/bone/kidney (ALPL) gene with highly variable clinical manifestations. Efforts have been made to collect cases with novel mutations and to examine how a missense mutation affects ALPL protein function, which remains difficult to predict. The present study investigated the underlying mechanism of ALPL dysfunction in a patient diagnosed with HP. Bidirectional sequencing of the ALPL gene was conducted in a 5‑year‑old Chinese girl preliminary diagnosed with childhood HP. Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping v2 (PolyPhen‑2) tools were used to forecast the impact of the mutation on protein function. Site‑directed mutagenesis was performed and transfected into cells to verify the role of the specific mutation. Furthermore, the mechanism of the impact was investigated via all‑atom molecular dynamics (MD) simulation. The patient demonstrated a compound heterozygote with two missense mutations in the ALPL gene, p.Trp29Arg and p.Ile395Val. Trp29 and Ile395 were determined to be 'tolerable' by SIFT, whereas they were 'possibly damaging' by PolyPhen‑2 in terms of conservation. Additionally, HEK293 cells were transfected with plasmids expressing wild type and/or mutated ALPL. Only 4.1% of ALP activity remained when Trp29 was substituted by Arg, whereas 19.1, 33.7, 50.1 and 7.6% ALP activity remained in cells expressing p.Ile395Val, wild type+p.Trp29Arg, wild type+p.Ile395Val and p.Trp29Arg+p.Ile395Val substitutions, respectively. All‑atom MD simulation demonstrated that the N‑terminal helix of mutated ALPL, where Trp29 is located, separated from the main body of the protein after 30 nsec, and moved freely. These results demonstrated that p.Trp29Arg, as a novel missense mutation in the ALPL gene, reduced the enzymatic activity of ALPL. This effect may be associated with an uncontrolled N‑terminal helix. These results provide novel information about the genetic basis of HP, and may facilitate the development of future therapies.

Project description:BackgroundMarfan syndrome (MFS) is a heritable disorder of connective tissue resulting from pathogenic variants of the fibrillin-1 gene (FBN1). Neonatal Marfan syndrome (nMFS) is rare and the most severe form of MFS, involving rapidly progressive cardiovascular dysfunction leading to death during early childhood. The constant enrichment of the nMFS mutation spectrum is helpful to improve our understanding of genotype-phenotype correlations in the disease. Herein, we report a novel dominant mutation in exon 26 of FBN1 (c.3331 T > C) in a sporadic case with nMFS.Case presentationAn 8-month-old Han Chinese girl presented with the classic nMFS phenotype, including prominent manifestations of bone overgrowth, aortic root dilatation, and multiple cardiac valve dysfunctions. Genetic analysis revealed that she was heterozygous for a de novo FBN1 missense mutation (c.3331 T > C). The mutation leads to the substitution of a highly conserved FBN1 cysteine residue (p.Cys1111Arg), which is likely to severely perturb the FBN1 structure because of an alteration of the disulfide bond pattern in the calcium-binding epidermal growth factor-like (cbEGF) 12 domain. This variant was absent in 208 ethnically matched controls, providing further evidence that it may be causative of nMFS. An analysis of nMFS-associated mutations from the UMD-FBN1 database indicates that those de novo mutations altering disulfide bonds or Ca(2+) binding sites of the cbEGF domains encoded by exons 25-33, and a lack of phenotypic heterogeneity may be associated with an increased risk for nMFS.ConclusionWe diagnosed an infant with rare nMFS showing rapidly progressive cardiovascular dysfunction and widely systemic features. As the only causal FBN1 mutation identified in the patient, the missense mutation c.3331 T > C (p.Cys1111Arg) was associated with the severe phenotype of MFS. However, the pathogenicity of the novel mutation needs further confirmation in other patients with nMFS. Our review of the prominent characteristics of nMFS mutations relative to classic or incomplete MFS-related mutations will be helpful for the recognition of novel nMFS-associated variants.

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A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

Publications

A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

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