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

Autor: Jinks RN; 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA rjinks@fandm.edu., Puffenberger EG; 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., Baple E; 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., Harding B; 6 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Crino P; 7 Shriners Hospital Paediatric Research Centre, Temple University School of Medicine, Philadelphia, PA 19140, USA., Fogo AB; 8 Division of Renal Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Wenger O; 9 New Leaf Clinic for Special Children, Mount Eaton, OH 44659, USA 10 Department of Paediatrics, Akron Children's Hospital, Akron, OH 44302, USA., Xin B; 11 DDC Clinic for Special Needs Children, Middlefield, OH 44062, USA., Koehler AE; 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA., McGlincy MH; 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA., Provencher MM; 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA., Smith JD; 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA., Tran L; 1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA., Al Turki S; 12 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK., Chioza BA; 13 Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter EX1 2LU, UK., Cross H; 14 Department of Ophthalmology, University of Arizona College of Medicine, Tucson, AZ 85711, USA., Harlalka GV; 13 Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter EX1 2LU, UK., Hurles ME; 12 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK., Maroofian R; 13 Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Exeter EX1 2LU, UK., Heaps AD; 2 Clinic for Special Children, Strasburg, PA 17579, USA., Morton MC; 2 Clinic for Special Children, Strasburg, PA 17579, USA., Stempak L; 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., Hildebrandt F; 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., Sadowski CE; 18 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Zaritsky J; 19 Department of Paediatrics, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA., Campellone K; 20 Department of Molecular and Cell Biology and Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA., Morton DH; 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., Wang H; 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., Crosby A; 3 RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK., Strauss KA; 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.
Jazyk: angličtina
Zdroj: Brain : a journal of neurology [Brain] 2015 Aug; Vol. 138 (Pt 8), pp. 2173-90. Date of Electronic Publication: 2015 Jun 11.
DOI: 10.1093/brain/awv153
Abstrakt: 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.
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Databáze: MEDLINE
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