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Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans

Sailan Wang1, Pernilla Nikamo1, Leena Laasonen2

  • 1Division of Dermatology and Venereology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

EMBO Molecular Medicine
|February 21, 2024
PubMed

Insights

Researchers identified rare variants in the NADPH oxidase 4 (NOX4) gene in patients with psoriatic arthritis mutilans (PAM). This finding links increased reactive oxygen species (ROS) to PAM, suggesting NOX4 as a potential susceptibility gene.

Area of Science:

  • Genetics
  • Rheumatology
  • Molecular Biology

Background:

  • Psoriatic arthritis mutilans (PAM) is a severe, rare form of psoriatic arthritis.
  • Characterized by joint erosions and osteolysis, its genetic basis and mechanisms remain unknown.
  • No susceptibility genes for PAM have been identified previously.

Purpose of the Study:

  • To investigate the genetic underpinnings of Psoriatic Arthritis Mutilans (PAM).
  • To identify potential susceptibility genes associated with the severe joint destruction seen in PAM.

Main Methods:

  • Massive parallel sequencing was performed on 61 patients from the PAM Nordic cohort.
  • In silico analysis predicted the pathogenicity of identified variants.
  • Functional studies included cell cultures, zebrafish models, and in vivo reactive oxygen species (ROS) measurements.

Main Results:

  • Rare variants in the NADPH oxidase 4 (NOX4) gene were identified in four PAM patients.
  • In silico predictions indicated these variants are potentially damaging.
  • Functional studies confirmed that NOX4 variants increase ROS levels in vitro and in vivo, implicating NOX4 in osteoclast differentiation and bone resorption.

Conclusions:

  • NADPH oxidase 4 (NOX4) is proposed as the first candidate susceptibility gene for Psoriatic Arthritis Mutilans (PAM).
  • The study establishes a link between elevated ROS levels due to NOX4 variants and PAM development.
  • This research offers a potential therapeutic target for PAM by focusing on ROS modulation.
Keywords:
Hydrogen PeroxideNADPH Oxidase 4 (NOX4)Osteoclast DifferentiationPsoriatic Arthritis MutilansReactive Oxygen Species (ROS)

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