Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of<i>WDR73</i>

Jinks, Robert N.; Puffenberger, Erik G.; Baple, Emma L.; Harding, Brian; Crino, Peter B.; Fogo, Agnes B.; Wenger, Olivia; Xin, Baozhong; Koehler, Alanna E.; McGlincy, Madeleine; Provencher, Margaret M.; Smith, Jeffrey D.; Tran, Linh; Turki, Saeed Al; Chioza, Barry A.; Cross, Harold E.; Harlalka, Gaurav V.; Hurles, Matthew E.; Maroofian, Reza; Heaps, Adam D.; Morton, Mary C.; Stempak, Lisa; Hildebrandt, Friedhelm; Sadowski, Carolin E.; Zaritsky, Joshua J.; Campellone, Kenneth; Morton, D. Holmes; Wang, Heng; Crosby, Andrew H.; Strauss, Kevin A.

doi:10.1093/brain/awv153

Cited by 63 publications

(65 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutated genes identified in GAMOS are now categorized into 3 groups: WDR73 , KEOPS‐complex subunit genes ( OSGEP, TP53RK, TPRKB , and LAGE3 ), and the nucleoporin genes ( NUP133 and NUP107 ). The WDR73 and KEOPS‐complex genes play a role in cell proliferation and the cell cycle, and NUP133 is also reportedly involved in the cell cycle . However, to our knowledge, the functional relationship between these 3 groups of proteins is not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recessive mutations were recently identified in OSGEP, TP53RK, TPRKB , and LAGE3 , which encode the 4 subunits of the KEOPS complex that is involved in universal post‐transcriptional modification of transfer RNA, gene transcription, and genome maintenance . Various neurological features were found in patients arising from mutations in the above genes: microcephaly, cerebellar hypoplasia, gyration abnormalities, thin corpus callosum, and/or optic atrophy …”

mentioning

confidence: 99%

See 1 more Smart Citation

Homozygous splicing mutation in NUP133 causes Galloway–Mowat syndrome

Fujita

Tsukaguchi

Koshimizu

et al. 2018

Annals of Neurology

View full text Add to dashboard Cite

Objective: Galloway-Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early onset nephrotic syndrome. Biallelic mutations in WDR73 and the 4 subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107kDa) mutation was identified in 4 GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroidresistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis. Methods: Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid-resistant nephrotic syndrome. Results: We identified a homozygous NUP133 mutation, c.3335-11T>A, which results in the insertion of 9bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the 3 examined patients. A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wild-type NUP133 mRNA but not by mutant mRNA. Interpretation: These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Homozygous splicing mutation in NUP133 causes Galloway–Mowat syndrome

Fujita

Tsukaguchi

Koshimizu

et al. 2018

Annals of Neurology

View full text Add to dashboard Cite

show abstract

“…Notably at locus 17q22 we observed a promoter variant (rs302875) which displays a strong eQTL effect (GTEx data, P =4.9 x 10 -7 ) on TEX14 (Testis-Expressed 14), which encodes an important regulator of kinetochore-microtubule assembly in testicular germ cells14,34,35. At new risk locus 15q25.2 we identified a nominal eQTL association (rs2304416, TCGA data, P =3.2 x 10 -2 ) and accompanying chromatin looping interaction with mitotic spindle assembly related gene WDR73 36 (Fig. 3b).…”

mentioning

confidence: 92%

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

et al. 2017

View full text Add to dashboard Cite

Genome-wide association studies (GWAS) have transformed our understanding of testicular germ cell tumour (TGCT) susceptibility but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, approximately doubling the number of known TGCT risk loci to 44. By performing in-situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions between all 44 TGCT risk SNPs and candidate causal genes. Our findings reveal widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis1. Defective microtubule assembly and dysregulation of KIT-MAPK signalling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

show abstract

“…Nucleation-promoting factors from the WASP family assimilate upstream signals and activate the Arp2/3 complex to drive actin assembly. The physiological importance of these factors is underscored by the observations that murine N-WASP, WAVE1, WAVE2, and WASH gene knockouts result in lethality [19,20,22,29], that mutations in human WAS give rise to immunodeficiencies [18,85], and that a mutation in WHAMM is found in patients with a neurodevelopmental/renal disorder [38,86]. All family members have been shown to influence cell motility, with at least 6 playing roles in membrane protrusion.…”

Section: Discussionmentioning

confidence: 99%

WHIMP links the actin nucleation machinery to Src-family kinase signaling during protrusion and motility

2020

View full text Add to dashboard Cite

Cell motility is governed by cooperation between the Arp2/3 complex and nucleation-promoting factors from the Wiskott-Aldrich Syndrome Protein (WASP) family, which together assemble actin filament networks to drive membrane protrusion. Here we identify WHIMP (WAVE Homology In Membrane Protrusions) as a new member of the WASP family. The Whimp gene is encoded on the X chromosome of a subset of mammals, including mice. Murine WHIMP promotes Arp2/3-dependent actin assembly, but is less potent than other nucleation factors. Nevertheless, WHIMP-mediated Arp2/3 activation enhances both plasma membrane ruffling and wound healing migration, whereas WHIMP depletion impairs protrusion and slows motility. WHIMP expression also increases Src-family kinase activity, and WHIMP-induced ruffles contain the additional nucleation-promoting factors WAVE1, WAVE2, and N-WASP, but not JMY or WASH. Perturbing the function of Src-family kinases, WAVE proteins, or Arp2/3 complex inhibits WHIMP-driven ruffling. These results suggest that WHIMP-associated actin assembly plays a direct role in membrane protrusion, but also results in feedback control of tyrosine kinase signaling to modulate the activation of multiple WASP-family members.

show abstract

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations ofWDR73

Cited by 63 publications

References 74 publications

Homozygous splicing mutation in NUP133 causes Galloway–Mowat syndrome

Homozygous splicing mutation in NUP133 causes Galloway–Mowat syndrome

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

WHIMP links the actin nucleation machinery to Src-family kinase signaling during protrusion and motility

Contact Info

Product

Resources

About