Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations ofWDR73
Year: 2015
Type: article
Study design: Observational Study
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 α-, β-, and γ-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 α- and β-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. Galloway-Mowat syndrome (GMS) is a neurodevelopmental disorder characterized by microcephaly, cerebellar hypoplasia, nephrosis, and profound intellectual disability. Jinks et al. extend the GMS spectrum by identifying a novel nephrocerebellar syndrome with selective striatal cholinergic interneuron loss and complete lateral geniculate nucleus delamination, caused by a frameshift mutation in WDR73.
Source: Brain
DOI: 10.1093/brain/awv153
Authors: Robert N. Jinks, Erik G. Puffenberger, Emma Baple, Brian Harding, Peter Crino, Agnes B. Fogo, Olivia Wenger, Baozhong Xin, Alanna E. Koehler, Madeleine H. McGlincy, Margaret M. Provencher, Jeffrey D. Smith, Linh Tran, Saeed Al Turki, Barry A. Chioza, Harold Cross, Gaurav V. Harlalka, Matthew E. Hurles, Reza Maroofian, Adam D. Heaps, Mary C. Morton, Lisa Stempak, Friedhelm Hildebrandt, Carolin E. Sadowski, Joshua Zaritsky, Kenneth Campellone, D. Holmes Morton, Heng Wang, Andrew Crosby, Kevin A. Strauss
Institutions: Franklin & Marshall College, Clinic for Special Children, Royal Devon & Exeter NHS Foundation Trust, Princess Anne Hospital, University of Southampton, Royal Devon University Healthcare NHS Foundation Trust, Children's Hospital of Philadelphia, University of Pennsylvania, Shriners Hospitals for Children - Philadelphia, Temple University, Vanderbilt University, Akron Children's Hospital, Wellcome Sanger Institute, University of Exeter, University of Arizona, University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, Case Western Reserve University, Boston Children's Hospital, Howard Hughes Medical Institute, Harvard University, Alfred I. duPont Hospital for Children, University of Connecticut, Lancaster General Hospital, Cleveland Clinic, Rainbow Babies & Children's Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,570
Funders: Howard Hughes Medical Institute, Broad Institute, Newlife the Charity for Disabled Children, National Institutes of Health, Medical Research Council, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1614887885, Cytoskeletal control of membrane remodeling, Functional characterization of the gene NPHP4, G3716821922, G3785326886, G395977854, G424839542, G5049616643, G5095395321, G5424594667, G6877149276, G6914090398, G714305199, Discover and functionally characterize full-penetrance causes of nephrosis / FSGS, G812892468, Novel genetics, pathobiology and therapy of nephronophthisis-related ciliopathies
OpenAlex ID: W2098540383