title: Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism.
abstract: BACKGROUND
  Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity.
  
  
  RESULTS
  Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast.
  
  
  CONCLUSIONS
  Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Ghada M H
authors.initials: GM
authors.lastname: Abdel-Salam
authors.affiliation: Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.|Current address: Department of Chemistry, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Guy
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Rana
authors.initials: R
authors.lastname: Alomar
authors.affiliation: Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hamid
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Hanan H
authors.initials: HH
authors.lastname: Afifi
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Samira I
authors.initials: SI
authors.lastname: Ismail
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Bayoumi A
authors.initials: BA
authors.lastname: Emam
authors.affiliation: Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Eric_Phizicky@URMC.Rochester.edu.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Phizicky
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@Kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@Kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D004392:Dwarfism / Q000209:etiology / Q000235:genetics*; D059472:Exome / Q000235:genetics; D019066:Facies; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008745:Methylation; D008831:Microcephaly / Q000209:etiology / Q000235:genetics*; D020125:Mutation, Missense; D012343:RNA, Transfer / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: C417912:WDR4 protein, human; D012343:RNA, Transfer; D019204:GTP-Binding Proteins