title: 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.
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, 84112, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Rope
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Rune
authors.initials: R
authors.lastname: Evjenth
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Xing
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Swensen
authors.forename: W Evan
authors.initials: WE
authors.lastname: Johnson
authors.forename: Barry
authors.initials: B
authors.lastname: Moore
authors.forename: Chad D
authors.initials: CD
authors.lastname: Huff
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Bird
authors.forename: John C
authors.initials: JC
authors.lastname: Carey
authors.forename: John M
authors.initials: JM
authors.lastname: Opitz
authors.forename: Cathy A
authors.initials: CA
authors.lastname: Stevens
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Christa
authors.initials: C
authors.lastname: Schank
authors.forename: Heidi Deborah
authors.initials: HD
authors.lastname: Fain
authors.forename: Reid
authors.initials: R
authors.lastname: Robison
authors.forename: Brian
authors.initials: B
authors.lastname: Dalley
authors.forename: Steven
authors.initials: S
authors.lastname: Chin
authors.forename: Sarah T
authors.initials: ST
authors.lastname: South
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Pysher
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Jorde
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Johan R
authors.initials: JR
authors.lastname: Lillehaug
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnesen
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000172:deficiency* / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D005091:Exons; D050172:Genes, X-Linked; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D010375:Pedigree; D010641:Phenotype
chemical_list: D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E