Abstract
BackgroundPrimordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity.ResultsTwo 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 (m7G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m7G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m7G46 modification causes a growth deficiency phenotype in yeast.ConclusionOur study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0779-x) contains supplementary material, which is available to authorized users.
Highlights
Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity
Primordial dwarfism (PD) is a term used to describe a wide range of phenotypes that have in common severe prenatal growth deficiency (>3 SD below the mean) that persists postnatally [1]
We show that the two families affected by this disorder map to WDR4, the human ortholog of Trm82, which is required for formation of the highly conserved m7G46 (7-methylguanosine) modification of tRNA
Summary
Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity. Primordial dwarfism (PD) is a term used to describe a wide range of phenotypes that have in common severe prenatal growth deficiency (>3 SD below the mean) that persists postnatally [1]. Our knowledge of the biology of tRNA modification comes primarily from work on the yeast Saccharomyces cerevisiae and other model organisms [15,16,17]. Modifications in the tRNA anticodon loop are critical for translational efficiency, frame maintenance, and fidelity, and lack of these modifications often leads to lethality, slow growth, and/or other phenotypic effects [16, 18]. Modifications to the body of the tRNA are generally involved in tRNA folding and stability [19,20,21,22], and lack of any of several different body modifications in yeast causes temperature sensitivity due to rapid tRNA decay (RTD) of specific tRNAs [23,24,25]
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