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

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.

The RNA modification landscape in human disease

“…Numerous genetic birth defects have been associated with mutations in RNA modification enzymes, such as the Cri du chat syndrome (NOP2/NOL1/p120/NSUN1) (Wu et al 2005), the Dubowitz syndrome (NSUN2) (Martinez et al 2012), the Noonan-like syndrome (NSUN2) (Fahiminiya et al 2014), or the William-Beuren syndrome (WBSCR20/WBSCR22/ NSUN5) (Doll and Grzeschik 2001). Furthermore, mutations in RNA modification enzymes have also been shown to cause developmental defects, such as Hutchinson-Gilford progeria syndrome (NAT10) (Larrieu et al 2014), and primordial dwarfism (WDR4) (Shaheen et al 2015). In addition, mutations in RNA modification enzymes can cause the spinal cord to expose outside the body like spina bifida (TRDMT1) (Franke et al 2009) and infant death (EMG1) (Armistead et al 2009).…”

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

“…Notably, defects in tRNA modification have emerged as the cause of diverse neurological and neurodevelopmental disorders, thereby highlighting the critical role of tRNA modification in human health and physiology (Angelova et al, 2018; Ramos & Fu, 2019). In particular, the brain appears to be sensitive to any perturbation in translation efficiency and fidelity brought about by defects in tRNA modifications, as evidenced from the numerous cognitive disorders linked to tRNA modification enzymes such as: the Elongator complex (Hawer et al, 2018; Kojic & Wainwright, 2016); ADAT3 (Alazami et al, 2013; El‐Hattab et al, 2016; Ramos, Han, et al, 2019); NSUN2 (Abbasi‐Moheb et al, 2012; Khan et al, 2012; Martinez et al, 2012); FTSJ1 (Dai et al, 2008; Freude et al, 2004; Froyen et al, 2007; Gong et al, 2008; Guy et al, 2015; Ramser et al, 2004; Takano et al, 2008); WDR4 (Chen et al, 2018; Shaheen et al, 2015; Trimouille et al, 2018); KEOPS complex (Braun et al, 2017); PUS3 (Abdelrahman, Al‐Shamsi, Ali, & Al‐Gazali, 2018; Shaheen, Han, et al, 2016); CTU2 (Shaheen, Al‐Salam, El‐Hattab, & Alkuraya, 2016; Shaheen, Mark, et al, 2019); TRMT10A (Gillis et al, 2014; Igoillo‐Esteve et al, 2013; Narayanan et al, 2015; Yew, McCreight, Colclough, Ellard, & Pearson, 2016; Zung et al, 2015); PUS7 (de Brouwer et al, 2018; Shaheen, Tasak, et al, 2019); and ALKBH8 (Monies, Vagbo, Al‐Owain, Alhomaidi, & Alkuraya, 2019).…”

Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment

“…To determine the region in WDR4 that is critical for PML binding, we performed a structural modeling of WDR4 using the tertiary structure of TRM82 (27), the yeast ortholog of WDR4, as a template. The WD-repeat domain of WDR4 adopts a 7-blade β-propeller structure, in which the WDxR motif is localized to the bottom surface of the β-propeller (Supplemental Figure 2A).…”