Functional characterization of a novel TP53RK mutation identified in a family with Galloway–Mowat syndrome

Abstract

Galloway-Mowat syndrome (GAMOS) is a very rare condition characterized by earlyonset nephrotic syndrome and microcephaly with variable neurologic features.While considerable genetic heterogeneity of GAMOS has been identified, the majority of cases are caused by pathogenic variants in genes encoding the four components of the Kinase, endopeptidase, and other proteins of small size (KEOPS) complex, one of which is TP53RK. Here we describe a 3-year-old male with progressive microcephaly, neurodevelopmental deficits, and glomerular proteinuria.He was found to carry a novel homozygous TP53RK missense variant, c.163C>G (p.Arg55Gly), which was considered as potentially disease-causing. We generated a morpholino tp53rk knockdown model in Xenopus laevis showing that the depletion of endogenous Tp53rk caused abnormal eye and head development. This phenotype could be rescued by the expression of human wildtype TP53RK but not by the c.163C>G mutant nor by another previously described GAMOS-associated mutant c.125G>A (p.Gly42Asp). These findings support the pathogenic role of the novel TP53RK variant.

Conservation and Diversification of tRNA t6A-Modifying Enzymes across the Three Domains of Life

“…Dysfunction of KEOPS complex abolishes the tRNA t 6 A formation in vivo [ 42 , 70 , 79 ], leads to shortened telomeres [ 41 , 109 ] and impairs protein synthesis in archaea and eukaryotes [ 56 , 110 ]. In humans, mutations of KEOPS genes are implicated in neurological disorders, including the Galloway–Mowat syndrome (GAMOS), which is characterized by early-onset steroid-resistant nephrotic syndrome combined with mesangial sclerosis microcephaly and brain anomalies [ 42 , 56 , 80 , 111 ].…”

“…Interestingly, an ATP hydrolysis by Bud32 is indispensably involved in t 6 A biosynthesis by yeast and archaean KEOPS [ 70 , 71 , 80 , 100 ]. Mutation of the strictly conserved aspartate acid residue (D127 of P. abyssi Bud32, D112 of M. jannaschii Bud32 and D161 of S. cerevisiae Bud32) abolishes ATPase activity of Bud32 and tRNA t 6 A-catalytic activity of KEOPS [ 70 , 71 , 72 ].…”

“…Posttranscriptional modifications of tRNAs regulate the translational efficiency and protein homeostasis [ 13 , 52 , 53 , 54 , 55 , 119 ]. The frequency of tRNA t 6 A modification varies among different types of cells and is higher in tissues and organs that are less tolerated to the translational deficiency [ 29 , 42 , 46 , 49 , 55 , 56 , 58 , 74 , 80 , 120 , 121 , 122 ]. In general, tRNA t 6 A and its biosynthetic enzymes (YRDC, KEOPS and OSGEPL1) are more abundant in energy-demanding mitochondria and highly proliferating cells in brain, kidney and liver ( Figure 3 A) [ 29 , 42 , 56 , 58 , 110 , 114 , 115 ].…”

“…The depletion of tRNA t 6 A leads to cell death or severe growing phenotypes via causing glitches of translation apparatus in the cytosol and in mitochondria [ 26 , 59 , 60 , 110 ]. In clinical cases, deregulation of tRNA t 6 A-biosynthetic machineries has been implicated in patients with mitochondrial diseases [ 29 ] and individuals with a range of congenital nephrotic syndromes [ 121 , 122 ], including GAMOS ( Table 5 ) [ 42 , 80 , 111 , 123 , 124 ].…”

“…In human podocytes, the knockdown of KEOPS subunit genes led to the loss of tRNA t 6 A, interfered with protein biosynthesis and led to activation of the unfolded protein response and endoplasmic reticulum stress [ 56 ]. In clinical studies, recessive pathogenic mutations in KEOPS-encoding genes have been found in sequence genomes of patients with GAMOS ( Figure 3 A and Table 5 ) [ 42 , 56 , 80 , 111 , 121 , 124 ]. Individuals with GAMOS also contain pathogenic missense variants of YRDC [ 42 ] and WDR4-a tRNA 7-methylguanosine (m 7 G) synthetase [ 128 , 129 ].…”