Genetic and clinical heterogeneity in eIF2B-related disorder.
Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.
Maletkovic
Jelena
J
Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC 20010, USA.
Schiffmann
Raphael
R
Gorospe
J Rafael
JR
Gordon
Erynn S
ES
Mintz
Michelle
M
Hoffman
Eric P
EP
Alper
Gulay
G
Lynch
David R
DR
Singhal
Bhim S
BS
Harding
Cary
C
Amartino
Hernan
H
Brown
Candida M
CM
Chan
Alicia
A
Renaud
Deborah
D
Geraghty
Michael
M
Jensen
Lloyd
L
Senbil
Nesrin
N
Kadom
Nadja
N
Nazarian
Javad
J
Yuanjian Feng
Zuyi Wang
Hartka
Thomas
T
Morizono
Hiroki
H
Vanderver
Adeline
A
D000293:Adolescent; D000328:Adult; D001927:Brain Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics; D040681:Structural Homology, Protein
D020717:Eukaryotic Initiation Factor-2B; D021122:Protein Subunits