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. CONCLUSION: 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 | Ranad Shaheen, Ghada M H Abdel-Salam, Michael P Guy, Rana Alomar, Mohamed S Abdel-Hamid, Hanan H Afifi, Samira I Ismail, Bayoumi A Emam, Eric M Phizicky, Fowzan S Alkuraya |
Journal | Genome biology
(Genome Biol)
Vol. 16
Pg. 210
(Sep 28 2015)
ISSN: 1474-760X [Electronic] England |
PMID | 26416026
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- WDR4 protein, human
- RNA, Transfer
- GTP-Binding Proteins
|
Topics |
- Dwarfism
(etiology, genetics)
- Exome
(genetics)
- Facies
- GTP-Binding Proteins
(genetics)
- Humans
- Methylation
- Microcephaly
(etiology, genetics)
- Mutation, Missense
- RNA, Transfer
(genetics)
- Saccharomyces cerevisiae
(genetics)
|