TY - JOUR
T1 - Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2
AU - Neilson, Derek E.
AU - Adams, Mark D.
AU - Orr, Caitlin M.D.
AU - Schelling, Deborah K.
AU - Eiben, Robert M.
AU - Kerr, Douglas S.
AU - Anderson, Jane
AU - Bassuk, Alexander G.
AU - Bye, Ann M.
AU - Childs, Anne-Marie
AU - Clarke, Antonia
AU - Crow, Yanick J.
AU - Di Rocco, Maja
AU - Dohna-Schwake, Christian
AU - Dueckers, Gregor
AU - Fasano, Alfonso E.
AU - Gika, Artemis D.
AU - Gionnis, Dimitris
AU - Gorman, Mark P.
AU - Grattan-Smith, Padraic J.
AU - Hackenberg, Annette
AU - Kuster, Alice
AU - Lentschig, Markus G.
AU - Lopez-Laso, Eduardo
AU - Marco, Elysa J.
AU - Mastroyianni, Sotiria
AU - Perrier, Julie
AU - Schmitt-Mechelke, Thomas
AU - Servidei, Serenella
AU - Skardoutsou, Angeliki
AU - Uldall, Peter
AU - Van Der Knaap, Marjo S.
AU - Goglin, Karrie C.
AU - Tefft, David L.
AU - Aubin, Cristin
AU - De Jager, Philip
AU - Hafler, David
AU - Warman, Matthew L.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Genetic Predisposition to Disease
KW - Influenza, Human
KW - Leukoencephalitis, Acute Hemorrhagic
KW - Molecular Chaperones
KW - Nuclear Pore Complex Proteins
KW - Genetic Predisposition to Disease
KW - Influenza, Human
KW - Leukoencephalitis, Acute Hemorrhagic
KW - Molecular Chaperones
KW - Nuclear Pore Complex Proteins
UR - http://hdl.handle.net/10807/15157
U2 - 10.1016/j.ajhg.2008.12.009
DO - 10.1016/j.ajhg.2008.12.009
M3 - Article
SN - 0002-9297
VL - 84
SP - 44
EP - 51
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
ER -