Novel Majeed syndrome causing LPIN2 mutations link bone inflammation to inflammatory M2 macrophages and accelerated osteoclastogenesis

Farzana Bhuyan; Adriana A de Jesus; Jacob Mitchell; Evgenia Leikina; Rachel VanTries; Ronit Herzog; Karen B Onel; Andrew Oler; Gina A Montealegre Sanchez; Kim A Johnson; Lena Bichell; Bernadette Marrero; Luis Fernandez De Castro; Yan Huang; Katherine R Calvo; Michael T Collins; Sundar Ganesan; Leonid V Chernomordik; Polly J Ferguson; Raphaela Goldbach-Mansky

doi:10.1002/art.41624

Journal article

Novel Majeed syndrome causing LPIN2 mutations link bone inflammation to inflammatory M2 macrophages and accelerated osteoclastogenesis

Farzana Bhuyan, Adriana A de Jesus, Jacob Mitchell, Evgenia Leikina, Rachel VanTries, Ronit Herzog, Karen B Onel, Andrew Oler, Gina A Montealegre Sanchez, Kim A Johnson, …

Arthritis & rheumatology (Hoboken, N.J.), Vol.73(6), pp.1021-1032

12/14/2020

DOI: 10.1002/art.41624

PMCID: PMC8252456

PMID: 33314777

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Abstract

We identified novel heterozygous LPIN2 mutations in a Majeed patient and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. Targeted genetic analysis, and functional studies assessing monocyte responses, macrophage differentiation and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to the IL-1 mediated diseases, NOMID and DIRA. A 4-year-old girl of mixed ethnic background, presented with sterile osteomyelitis, and elevated acute phase reactants and harbored a 17.8 Kb deletion on the maternal LPIN2 allele, and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. She achieved long-lasting remission on IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages in the Majeed, NOMID and DIRA patients had elevated caspase-1 activity and secreted IL-1β levels. In contrast, LPS stimulated monocyte-derived M2-like macrophages from the Majeed patient released higher levels of osteoclastogenic mediators (IL-8, IL-6, TNFα, CCL2, MIP-1α/β b, CXCL8 and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the Majeed patient was associated with higher NFATc1 levels, enhanced JNK/MAP kinase, and reduced Src kinase activation and partially responded to JNK inhibiton and IL-1 but not IL-6 blockade. We report two novel compound heterozygous disease-causing mutations in LPIN2 in a US patient with Majeed syndrome. LPIN2 deficiency drives differentiation of pro-inflammatory M2-macrophages and enhances intrinsic osteoclastogenesis thus providing a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1 mediated autoinflammatory diseases.

Sterile osteomyelitis

autoinflammatory bone disease

SNP array

LPIN2

Majeed syndrome

Details

Title: Subtitle: Novel Majeed syndrome causing LPIN2 mutations link bone inflammation to inflammatory M2 macrophages and accelerated osteoclastogenesis
Creators: Farzana Bhuyan - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Adriana A de Jesus - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Jacob Mitchell - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Evgenia Leikina - Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA
Rachel VanTries - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Ronit Herzog - NYU Langone Medical Center, New York, New York, United States
Karen B Onel - Department of Pediatrics, Hospital of Special Surgery, New York, New York, United States
Andrew Oler - Bioinformatics and Computational Biosciences Branch (BCBB), OCICB, NIAID, NIH, Bethesda, Maryland, United States
Gina A Montealegre Sanchez - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Kim A Johnson - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Lena Bichell - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Bernadette Marrero - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Luis Fernandez De Castro - NIDCR, NIH, Bethesda, Maryland, United States
Yan Huang - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Katherine R Calvo - Department of Laboratory Medicine (DLM), Clinical Center, NIH, Bethesda, Maryland, United States
Michael T Collins - NIDCR, NIH, Bethesda, Maryland, United States
Sundar Ganesan - Research Technologies Branch (RTB), NIAID, Bethesda, Maryland, United States
Leonid V Chernomordik - Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA
Polly J Ferguson - Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
Raphaela Goldbach-Mansky - Translational Autoinflammatory Diseases Section (TADS), NIAID, NIH, Bethesda, Maryland, USA
Resource Type: Journal article
Publication Details: Arthritis & rheumatology (Hoboken, N.J.), Vol.73(6), pp.1021-1032
DOI: 10.1002/art.41624
PMID: 33314777
PMCID: PMC8252456
NLM abbreviation: Arthritis Rheumatol
ISSN: 2326-5191
eISSN: 2326-5205
Publisher: United States
Grant note: DOI: 10.13039/100009633, name: Eunice Kennedy Shriver National Institute of Child Health and Human Development; DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases, award: R01AR059703; DOI: 10.13039/100006492, name: Division of Intramural Research, National Institute of Allergy and Infectious Diseases
Language: English
Date published: 12/14/2020
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology
Record Identifier: 9984071735002771

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