Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome

Abstract

Dubowitz Syndrome is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies, but causes are still unknown. We studied a multiplex consanguineous family with many features of Dubowitz syndrome using whole exome sequencing and identified a splice mutation in NSUN2, encoding a conserved RNA methyltransferase. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentations that can include chromosomal instability and immunological defects. Patient cells displayed loss of NSUN2-specific methylation at two residues of the aspartate tRNA. Our findings establish NSUN2 as the first causal gene with relationship to the Dubowitz syndrome spectrum phenotype.

Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes

“…This list includes intellectual disability associated with a point mutation in hADAT3 , the predicted homolog of a subunit of the yeast tRNA A 34 deaminase (Alazami et al 2013); a frameshift mutation in hTRMT1 (Najmabadi et al 2011), which has tRNA m 2,2 G 26 (N 2 ,N 2 -dimethylguanosine) methyltransferase activity (Liu and Strâby 2000); mutations in NSUN2 (AbbasiMoheb et al 2012;Khan et al 2012;Martinez et al 2012), which modifies C 34 , C 48 , C 49 , and C 50 on target tRNAs to m 5 C; and mutations in hELP2 (Najmabadi et al 2011), a member of the ELP complex responsible for formation of the cm 5 U moiety found on mcm 5 U 34 , ncm 5 U 34 , mcm 5 s 2 U 34 and related modifications. In addition, familial disautonomia is associated with mutations in hELP1 (IKBAKP) (Anderson et al 2001).…”

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).…”

Post-transcriptional modifications in development and stem cells

“…Consistent with this expression pattern, loss-of-function of NSUN2 is not lethal but causes neurodevelopmental deficits in the fly, mouse and human (Abbasi-Moheb et al, 2012;Blanco et al, 2014;Khan et al, 2012;Komara et al, 2015;Martinez et al, 2012). Lack of NSUN2 results in complete loss of m 5 C in the vast majority of transcribed tRNAs and causes increased angiogenin-induced tRNA cleavage leading to the accumulation of 5′ tRNA-derived small non-coding RNAs (Blanco et al, , 2014.…”