Mutation in WDR4 impairs tRNA m7G46 methylation and causes a distinct form of microcephalic primordial dwarfism

• DOI: 10.1186/s13059-015-0779-x
• Publication Date: 2015-09-28T10:43:21Z
• Authors: Ranad Shaheen; Ghada M H Abdel-S...; Michael P. Guy; Rana Alomar; Mohamed S. Abdel-...; Hanan H. Afifi; Samira I. Ismail; Bayoumi A. Emam; Eric M. Phizicky; Fowzan S. Alkuraya
• Keywords: Dwarfism; Microcephaly

Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, characterized by marked clinical genetic heterogeneity. Two presumably unrelated consanguineous families presented with an apparently novel form primordial in which severe deficiency accompanied distinct facial dysmorphism, brain malformation (microcephaly, agenesis corpus callosum, simplified gyration), encephalopathy seizures. Combined autozygome/exome analysis revealed missense mutation WDR4 as the likely causal variant. human ortholog yeast Trm82, essential component Trm8/Trm82 holoenzyme that effects highly conserved specific (m7G46) methylation tRNA. The corresponding result significant reduction m7G46 tRNA species, provides potential mechanism for associated this lesion, since reduced modification causes phenotype yeast. Our study expands number biological pathways underlying adds to growing list diseases linked abnormal modification.