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

2.50
Hdl Handle:
http://hdl.handle.net/11287/594019
Title:
Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73
Authors:
Jinks, R. N.; Puffenberger, E. G.; Baple, E.; Harding, B.; Crino, P.; Fogo, A. B.; Wenger, O.; Xin, B.; Koehler, A. E.; McGlincy, M. H.; Provencher, M. M.; Smith, J. D.; Tran, L.; Al Turki, S.; Chioza, Barry A.; Cross, H.; Harlalka, G. V.; Hurles, M. E.; Maroofian, R.; Heaps, A. D.; Morton, M. C.; Stempak, L.; Hildebrandt, F.; Sadowski, C. E.; Zaritsky, J.; Campellone, K.; Morton, D. H.; Wang, H.; Crosby, Andrew; Strauss, K. A.
Abstract:
We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with alpha-, beta-, and gamma-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with alpha- and beta-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.
Citation:
Brain. 2015 Aug;138(Pt 8):2173-90.
Publisher:
Oxford Journals
Journal:
Brain : a journal of neurology
Issue Date:
11-Jun-2015
URI:
http://hdl.handle.net/11287/594019
DOI:
10.1093/brain/awv153
PubMed ID:
26070982
Additional Links:
http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=26070982
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1460-2156
Appears in Collections:
2015 RD&E publications; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorJinks, R. N.en
dc.contributor.authorPuffenberger, E. G.en
dc.contributor.authorBaple, E.en
dc.contributor.authorHarding, B.en
dc.contributor.authorCrino, P.en
dc.contributor.authorFogo, A. B.en
dc.contributor.authorWenger, O.en
dc.contributor.authorXin, B.en
dc.contributor.authorKoehler, A. E.en
dc.contributor.authorMcGlincy, M. H.en
dc.contributor.authorProvencher, M. M.en
dc.contributor.authorSmith, J. D.en
dc.contributor.authorTran, L.en
dc.contributor.authorAl Turki, S.en
dc.contributor.authorChioza, Barry A.en
dc.contributor.authorCross, H.en
dc.contributor.authorHarlalka, G. V.en
dc.contributor.authorHurles, M. E.en
dc.contributor.authorMaroofian, R.en
dc.contributor.authorHeaps, A. D.en
dc.contributor.authorMorton, M. C.en
dc.contributor.authorStempak, L.en
dc.contributor.authorHildebrandt, F.en
dc.contributor.authorSadowski, C. E.en
dc.contributor.authorZaritsky, J.en
dc.contributor.authorCampellone, K.en
dc.contributor.authorMorton, D. H.en
dc.contributor.authorWang, H.en
dc.contributor.authorCrosby, Andrewen
dc.contributor.authorStrauss, K. A.en
dc.date.accessioned2016-01-19T12:38:40Zen
dc.date.available2016-01-19T12:38:40Zen
dc.date.issued2015-06-11en
dc.identifier.citationBrain. 2015 Aug;138(Pt 8):2173-90.en
dc.identifier.issn1460-2156en
dc.identifier.pmid26070982en
dc.identifier.doi10.1093/brain/awv153en
dc.identifier.urihttp://hdl.handle.net/11287/594019en
dc.description.abstractWe describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with alpha-, beta-, and gamma-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with alpha- and beta-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.en
dc.language.isoengen
dc.publisherOxford Journalsen
dc.relation.urlhttp://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=26070982en
dc.titleRecessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73en
dc.typeJournal Articleen
dc.typeResearch Support, N.I.H., Extramuralen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalBrain : a journal of neurologyen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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