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Am J Hum Genet. 2011 Jul 15;89(1):28-43. doi: 10.1016/j.ajhg.2011.05.017. Epub 2011 Jun 23.

Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.

Author information

1
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, 84112, USA.

Erratum in

  • Am J Hum Genet. 2011 Aug 12;89(2):345.

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.

PMID:
21700266
PMCID:
PMC3135802
DOI:
10.1016/j.ajhg.2011.05.017
[Indexed for MEDLINE]
Free PMC Article

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