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

Rope, Alan F., Wang, Kai, Evjenth, Rune, Xing, Jinchuan, Johnston, Jennifer J., Swensen, Jeffrey J., Johnson, W. Evan, Moore, Barry, Huff, Chad D., Bird, Lynne M., Carey, John C., Opitz, John M., Stevens, Cathy A., Jiang, Tao, Schank, Christa, Fain, Heidi Deborah, Robison, Reid, Dalley, Brian, Chin, Steven, South, Sarah T., Pysher, Theodore J., Jorde, Lynn B., Hakonarson, Hakon, Lillehaug, Johan R., Biesecker, Leslie G., Yandell, Mark, Arnesen, Thomas, Lyon, Gholson J. (2011) Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. American Journal of Human Genetics, 89 (1). pp. 28-43. ISSN 0002-9297

URL: http://www.ncbi.nlm.nih.gov/pubmed/21700266
DOI: 10.1016/j.ajhg.2011.05.017

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.

Item Type: Paper
Uncontrolled Keywords: Acetylation Acetyltransferases Chromosomes, Human, X Exons Genes, X-Linked Haplotypes Humans Infant, Newborn Male Mutation Pedigree Phenotype
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > SNP
Investigative techniques and equipment > whole exome sequencing
Investigative techniques and equipment > assays > whole exome sequencing
CSHL Authors:
Communities: CSHL labs > Lyon lab
Depositing User: Matt Covey
Date Deposited: 10 Dec 2012 20:13
Last Modified: 10 Dec 2012 21:17
PMCID: PMC3135802
URI: http://repository.cshl.edu/id/eprint/26300

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