Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2.
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.
Neilson
Derek E
DE
Department of Genetics, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH 44106, USA. derek.neilson@cchmc.org
Adams
Mark D
MD
Orr
Caitlin M D
CM
Schelling
Deborah K
DK
Eiben
Robert M
RM
Kerr
Douglas S
DS
Anderson
Jane
J
Bassuk
Alexander G
AG
Bye
Ann M
AM
Childs
Anne-Marie
AM
Clarke
Antonia
A
Crow
Yanick J
YJ
Di Rocco
Maja
M
Dohna-Schwake
Christian
C
Dueckers
Gregor
G
Fasano
Alfonso E
AE
Gika
Artemis D
AD
Gionnis
Dimitris
D
Gorman
Mark P
MP
Grattan-Smith
Padraic J
PJ
Hackenberg
Annette
A
Kuster
Alice
A
Lentschig
Markus G
MG
Lopez-Laso
Eduardo
E
Marco
Elysa J
EJ
Mastroyianni
Sotiria
S
Perrier
Julie
J
Schmitt-Mechelke
Thomas
T
Servidei
Serenella
S
Skardoutsou
Angeliki
A
Uldall
Peter
P
van der Knaap
Marjo S
MS
Goglin
Karrie C
KC
Tefft
David L
DL
Aubin
Cristin
C
de Jager
Philip
P
Hafler
David
D
Warman
Matthew L
ML
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
D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; C094493:ran-binding protein 2