title: Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.
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.
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA rjinks@fandm.edu.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jinks
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA 2 Clinic for Special Children, Strasburg, PA 17579, USA.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.affiliation: 3 RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK 4 Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, UK 5 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Baple
authors.affiliation: 6 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Harding
authors.affiliation: 7 Shriners Hospital Paediatric Research Centre, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Crino
authors.affiliation: 8 Division of Renal Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: 9 New Leaf Clinic for Special Children, Mount Eaton, OH 44659, USA 10 Department of Paediatrics, Akron Children's Hospital, Akron, OH 44302, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Wenger
authors.affiliation: 11 DDC Clinic for Special Needs Children, Middlefield, OH 44062, USA.
authors.forename: Baozhong
authors.initials: B
authors.lastname: Xin
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA.
authors.forename: Alanna E
authors.initials: AE
authors.lastname: Koehler
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA.
authors.forename: Madeleine H
authors.initials: MH
authors.lastname: McGlincy
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Provencher
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Tran
authors.affiliation: 12 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Saeed
authors.initials: S
authors.lastname: Al Turki
authors.affiliation: 13 Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter EX1 2LU, UK.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Chioza
authors.affiliation: 14 Department of Ophthalmology, University of Arizona College of Medicine, Tucson, AZ 85711, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Cross
authors.affiliation: 13 Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter EX1 2LU, UK.
authors.forename: Gaurav V
authors.initials: GV
authors.lastname: Harlalka
authors.affiliation: 12 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: 13 Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter EX1 2LU, UK.
authors.forename: Reza
authors.initials: R
authors.lastname: Maroofian
authors.affiliation: 2 Clinic for Special Children, Strasburg, PA 17579, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Heaps
authors.affiliation: 2 Clinic for Special Children, Strasburg, PA 17579, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Morton
authors.affiliation: 15 Department of Pathology, University Hospitals Case Medical Centre, Cleveland, OH 44106, USA 16 Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stempak
authors.affiliation: 17 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA 18 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: 18 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: 19 Department of Paediatrics, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Zaritsky
authors.affiliation: 20 Department of Molecular and Cell Biology and Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Campellone
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA 2 Clinic for Special Children, Strasburg, PA 17579, USA 21 Lancaster General Hospital, Lancaster, PA 17602, USA.
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
authors.affiliation: 11 DDC Clinic for Special Needs Children, Middlefield, OH 44062, USA 22 Department of Paediatrics, Rainbow Babies and Children's Hospital and Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.affiliation: 3 RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Crosby
authors.affiliation: 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA 2 Clinic for Special Children, Strasburg, PA 17579, USA 21 Lancaster General Hospital, Lancaster, PA 17602, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism; D006551:Hernia, Hiatal / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009401:Nephrosis / Q000235:genetics*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics; D055815:Young Adult
chemical_list: D011506:Proteins; D014404:Tubulin; C000595586:WDR73 protein, human
keywords: cerebellar hypoplasia; mTOR; mitosis; nephrosis; progressive microcephaly