Abstract

PurposeN-terminal acetyltransferases modify proteins by adding an acetylmoiety to the first amino acid and are vital for protein and cell function. TheNatB complex acetylates 20% of the human proteome and is composed of thecatalytic subunit NAA20 and the auxiliary subunit NAA25. In five individualswith overlapping phenotypes, we identified recessive homozygous missensevariants in NAA20. MethodsTwo different NAA20 variants wereidentified in affected individuals in two consanguineous families by exome andgenome sequencing. Biochemical studies were employed to assess the impact of theNAA20 variants on NatB complex formationand catalytic activity. ResultsTwo homozygous variants, NAA20p.Met54Val and p.Ala80Val (GenBank: NM_016100.4, c.160A>G andc.239C>T), segregated with affected individuals in two unrelatedfamilies presenting with developmental delay, intellectual disability, andmicrocephaly. Both NAA20-M54V and NAA20-A80V were impaired in their capacity toform a NatB complex with NAA25, and in vitro acetylation assays revealed reducedcatalytic activities toward different NatB substrates. Thus, both NAA20 variantsare impaired in their ability to perform cellular NatB-mediated N-terminalacetylation. ConclusionWe present here a report of pathogenic NAA20 variants causing human disease and data supporting anessential role for NatB-mediated N-terminal acetylation in human development andphysiology. Graphical Abstract [Display omitted]

Highlights

  • N-terminal acetylation is a common protein modification in eukaryotes, and approximately 80% of all human proteins carry this modification [1, 2]

  • We report here five affected individuals of two unrelated families presenting with developmental delay (DD), intellectual disability (ID), and microcephaly

  • Genetic findings The index case in family 1, a 13-year-old female (F1:V.2) (Fig. 1a) of Saudi origin, was referred for neuropsychological evaluation for baseline cognitive assessment because of her global DD and significant ID. She is the eldest of three siblings, with a healthy sister and a brother suffering from DD and ID (F1:V.4)

Read more

Summary

INTRODUCTION

N-terminal acetylation is a common protein modification in eukaryotes, and approximately 80% of all human proteins carry this modification [1, 2]. N-terminal acetylation may have a range of functional consequences for the modified proteins including stability/degradation, subcellular targeting, and complex formation [1]. NatB is one of the major eukaryotic N-terminal acetyltransferases (NATs) acetylating around 20% of the human proteome in a cotranslational manner. Proteins harboring Met-Glu-, Met-Asp-, Met-Gln-, and Met-Asn-N-termini are substrates of NatB [3]. No genetic disease has so far been linked to pathogenic variants of the NAA20 or NAA25 genes. Protein studies revealed impaired functionality of both identified variants supporting that reduced cellular N-terminal acetylation is causative for disease

MATERIALS AND METHODS
RESULTS
DISCUSSION

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.