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

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73
Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73
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 ?-, ?-, and ?-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 ?- and ?-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
0006-8950
2173-2190
Jinks, R.N.
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Puffenberger, E.G.
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Baple, E.
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Harding, B.
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Crino, P.
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Fogo, A.B.
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Wenger, O.
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Xin, B.
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Koehler, A.E.
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McGlincy, M.H.
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Provencher, M.M.
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Smith, J.D.
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Tran, L.
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Al Turki, S.
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Chioza, B. A.
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Cross, H.
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Harlalka, G. V.
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Hurles, M. E.
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Maroofian, R.
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Heaps, A. D.
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Morton, M. C.
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Stempak, L.
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Hildebrandt, F.
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Sadowski, C. E.
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Zaritsky, J.
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Campellone, K.
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Morton, D. H.
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Wang, H.
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Crosby, A.
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Strauss, K. A.
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Jinks, R.N.
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Puffenberger, E.G.
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Baple, E.
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Harding, B.
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Crino, P.
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Fogo, A.B.
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Wenger, O.
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Xin, B.
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Koehler, A.E.
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McGlincy, M.H.
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Provencher, M.M.
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Smith, J.D.
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Tran, L.
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Al Turki, S.
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Chioza, B. A.
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Cross, H.
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Harlalka, G. V.
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Hurles, M. E.
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Maroofian, R.
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Heaps, A. D.
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Morton, M. C.
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Stempak, L.
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Hildebrandt, F.
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Sadowski, C. E.
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Zaritsky, J.
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Campellone, K.
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Morton, D. H.
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Wang, H.
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Crosby, A.
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Strauss, K. A.
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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, B. 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, A. and Strauss, K. A. (2015) Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73. Brain, 138 (Part 8), 2173-2190. (doi:10.1093/brain/awv153). (PMID:26070982)

Record type: Article

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 ?-, ?-, and ?-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 ?- and ?-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

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Accepted/In Press date: 14 April 2015
e-pub ahead of print date: 11 June 2015
Published date: August 2015
Organisations: Human Development & Health

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Local EPrints ID: 378135
URI: http://eprints.soton.ac.uk/id/eprint/378135
ISSN: 0006-8950
PURE UUID: 8d494531-fe96-47cb-b52a-5825f4e14b49

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Date deposited: 25 Jun 2015 10:06
Last modified: 14 Mar 2024 20:18

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Contributors

Author: R.N. Jinks
Author: E.G. Puffenberger
Author: E. Baple
Author: B. Harding
Author: P. Crino
Author: A.B. Fogo
Author: O. Wenger
Author: B. Xin
Author: A.E. Koehler
Author: M.H. McGlincy
Author: M.M. Provencher
Author: J.D. Smith
Author: L. Tran
Author: S. Al Turki
Author: B. A. Chioza
Author: H. Cross
Author: G. V. Harlalka
Author: M. E. Hurles
Author: R. Maroofian
Author: A. D. Heaps
Author: M. C. Morton
Author: L. Stempak
Author: F. Hildebrandt
Author: C. E. Sadowski
Author: J. Zaritsky
Author: K. Campellone
Author: D. H. Morton
Author: H. Wang
Author: A. Crosby
Author: K. A. Strauss

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