Using VAAST to Identify an X-Linked Disorder Resulting in Lethality in Male Infants Due to N-Terminal Acetyltransferase Deficiency

Abstract

We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.

A public resource facilitating clinical use of genomes

“…Early versions of our methods have already been used by other groups in their own genome research and interpretations (9,(12)(13)(14). Unlike many published genome interpretation efforts, which have focused on discovery of novel pathogenic variants in patients with genetic disease (15)(16)(17)(18)(19), this pilot focuses on 10 individuals not believed to have such diseases. As cohorts with heritable medical conditions join the PGP, our research will extend to disease-focused interpretations.…”

Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-α-Acetylation Features

“…Partial inactivation induces a number of metabolic disorders and apoptosis in mammalian cells (25)(26)(27)(28)(29). A recent study on recessive male infant lethality identifies a specific mutation of the NatA catalytic subunit (S37P variant) (24). This altered complex still displays 60 -80% of the wild type NatA activity but appears to be lethal within few days after birth.…”

“…Any gene inactivation of any components of the Nat complex is associated with oncogenesis and cell division defects in humans (21)(22)(23)(24). Partial inactivation induces a number of metabolic disorders and apoptosis in mammalian cells (25)(26)(27)(28)(29).…”

N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB

“…However, an increasing number of reports indicate that Nt-acetylation is essential for higher eukaryotes, but less critical for normal growth in yeast (9)(10)(11)(12). Functionally, Nt-acetylation was found to regulate a variety of protein features (13), including the degradation (at least in yeast) of some Nt-acetylated proteins by a new branch of the Nend-rule pathway (14) and the ability of Nt-acetylation to inhibit protein translocation into the endoplasmic reticulum (15).…”