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 28years) 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 28years, 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 Purkinjecell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateralgeniculate 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 singlenovel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebralcortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with a-, b-, 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 a- and b-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygousfor WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend theGalloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.