# Monoallelic mutations in MMD2 cause autosomal dominant aggressive periodontitis

## TL;DR

Mutations in the MMD2 gene impair neutrophil function, leading to a hereditary form of aggressive periodontitis.

## Contribution

First identification of MMD2 mutations as the cause of autosomal dominant aggressive periodontitis.

## Key findings

- Monoallelic MMD2 mutations disrupt Ras/ERK signaling in neutrophils.
- Impaired neutrophil chemotaxis and Golgi protein abnormalities were observed in patients.
- MMD2 mutations in mice caused alveolar bone loss and chemotaxis defects.

## Abstract

Monoallelic mutations, p.A116V and p.R126P, in MMD2 disturb fMLP-induced activation of Ras/ERK signaling and underlie the impairment of neutrophil chemotaxis, which leads to the development of the autosomal dominant form of aggressive periodontitis.

Aggressive periodontitis causes rapid destruction of periodontal tissue. It occurs at a young age with familial clustering. We report on the first time on molecular and cellular basis of a Mendelian form of autosomal dominant aggressive periodontitis. Monoallelic mutations in the monocyte to macrophage differentiation-associated 2 (MMD2) gene, encoding MMD2, in two Japanese families with autosomal dominant aggressive periodontitis are identified. Mutations, c.347 C>T (p.A116V) and c.377 G>C (p.R126P) in MMD2, disturbed fMLP-induced activation of Ras/ERK signaling. Additionally, abnormalities in the proteins of Golgi apparatus, a crucial contributor to innate immune signaling pathways, were identified in patients’ neutrophils. The knock-in and knockout mice exhibited alveolar bone loss by ligature-induced periodontitis, along with impaired fMLP-induced chemotaxis, as found in the patients with MMD2 mutation. Our studies revealed that monoallelic mutations in MMD2 underlie the impairment of neutrophil chemotaxis, which leads to the development of autosomal dominant aggressive periodontitis.