NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay

Irena J J Muffels; Elsa Wiame; Sabine A Fuchs; Maarten P G Massink; Holger Rehmann; Jiska L I Musch; Gijs Van Haaften; Didier Vertommen; Emile van Schaftingen; Peter M van Hasselt

doi:10.1093/braincomms/fcab256

NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay

Brain Commun. 2021 Oct 26;3(4):fcab256. doi: 10.1093/braincomms/fcab256. eCollection 2021.

Affiliations

¹ Department of Metabolic Diseases, Division of Pediatrics, Wilhelmina Children's Hospital University Medical Centre Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands.
² Laboratoire de biologie moléculaire, UCLouvain-Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium.
³ Department of Genetics, Section of Genome Diagnostics, Division Laboratories, Pharmacy and Biomedical Genetics, 3584 CX Utrecht, the Netherlands.
⁴ Department of Energy and Biotechnology, Flensburg University of Applied Sciences, 24943 Flensburg, Germany.
⁵ Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, 3584 CX Utrecht, the Netherlands.
⁶ Mass Spectrometry Platform, de Duve Institute, UCLouvain, 1200 Brussels, Belgium.
⁷ Laboratory of Physiological Chemistry, De Duve Institute, UCLouvain, 1200 Brussels, Belgium.

Abstract

The recent identification of NAA80/NAT6 as the enzyme that acetylates actins generated new insight into the process of post-translational actin modifications; however, the role of NAA80 in human physiology and pathology has not been clarified yet. We report two individuals from a single family harbouring a homozygous c.389T>C, p.(Leu130Pro) NAA80 genetic variant. Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay and mild proximal and axial muscle weakness. Based on the molecular structure, we predicted and confirmed the NAA80 c.389T>C, p.(Leu130Pro) variant to result in protein destabilization, causing severely decreased NAA80 protein availability. Concurrently, individuals exhibited a ∼50% decrease of actin acetylation. NAA80 individual derived fibroblasts and peripheral blood mononuclear cells showed increased migration, increased filopodia counts and increased levels of polymerized actin, in agreement with previous observations in NAA80 knock-out cells. Furthermore, the significant clinical overlap between NAA80 individuals and individuals with pathogenic variants in several actin subtypes reflects the general importance of controlled actin dynamics for the inner ear, brain and muscle. Taken together, we describe a new syndrome, caused by NAA80 genetic variants leading to decreased actin acetylation and disrupted associated molecular functions. Our work suggests a crucial role for NAA80-mediated actin dynamics in neuronal health, muscle health and hearing.

Keywords: Baraitser-Winter; actin acetylation; actin dynamics; hearing loss; post-translational actin modifications.