title: Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2.
abstract: Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA. derek.neilson@cchmc.org
authors.forename: Derek E
authors.initials: DE
authors.lastname: Neilson
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.forename: Caitlin M D
authors.initials: CM
authors.lastname: Orr
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Schelling
authors.forename: Robert M
authors.initials: RM
authors.lastname: Eiben
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kerr
authors.forename: Jane
authors.initials: J
authors.lastname: Anderson
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bye
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Childs
authors.forename: Antonia
authors.initials: A
authors.lastname: Clarke
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Christian
authors.initials: C
authors.lastname: Dohna-Schwake
authors.forename: Gregor
authors.initials: G
authors.lastname: Dueckers
authors.forename: Alfonso E
authors.initials: AE
authors.lastname: Fasano
authors.forename: Artemis D
authors.initials: AD
authors.lastname: Gika
authors.forename: Dimitris
authors.initials: D
authors.lastname: Gionnis
authors.forename: Mark P
authors.initials: MP
authors.lastname: Gorman
authors.forename: Padraic J
authors.initials: PJ
authors.lastname: Grattan-Smith
authors.forename: Annette
authors.initials: A
authors.lastname: Hackenberg
authors.forename: Alice
authors.initials: A
authors.lastname: Kuster
authors.forename: Markus G
authors.initials: MG
authors.lastname: Lentschig
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Laso
authors.forename: Elysa J
authors.initials: EJ
authors.lastname: Marco
authors.forename: Sotiria
authors.initials: S
authors.lastname: Mastroyianni
authors.forename: Julie
authors.initials: J
authors.lastname: Perrier
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitt-Mechelke
authors.forename: Serenella
authors.initials: S
authors.lastname: Servidei
authors.forename: Angeliki
authors.initials: A
authors.lastname: Skardoutsou
authors.forename: Peter
authors.initials: P
authors.lastname: Uldall
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Karrie C
authors.initials: KC
authors.lastname: Goglin
authors.forename: David L
authors.initials: DL
authors.lastname: Tefft
authors.forename: Cristin
authors.initials: C
authors.lastname: Aubin
authors.forename: Philip
authors.initials: P
authors.lastname: de Jager
authors.forename: David
authors.initials: D
authors.lastname: Hafler
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
mesh_terms: D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D007251:Influenza, Human / Q000150:complications; D004684:Leukoencephalitis, Acute Hemorrhagic / Q000209:etiology / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D020125:Mutation, Missense; D009177:Mycoplasma pneumoniae; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D018184:Paramyxoviridae Infections / Q000150:complications; D010375:Pedigree; D011019:Pneumonia, Mycoplasma / Q000150:complications; D012008:Recurrence
chemical_list: D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; C094493:ran-binding protein 2