Department of Neurological Surgery; Department of Radiology
Amino Acids, Peptides, and Proteins | Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology | Neurosurgery
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6-fold and 2.7-fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol-anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol-anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.
CWH43, GPI-anchored protein, hydrocephalus, normal pressure hydrocephalus
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Copyright 2021 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
Yang HW, Lee S, Yang D, Dai H, Zhang Y, Han L, Zhao S, Zhang S, Ma Y, Johnson MF, Rattray AK, Johnson TA, Wang G, Zheng S, Carroll RS, Park PJ, Johnson MD. Deletions in CWH43 cause idiopathic normal pressure hydrocephalus. EMBO Mol Med. 2021 Jan 18:e13249. doi: 10.15252/emmm.202013249. Epub ahead of print. PMID: 33459505. Link to article on publisher's site
EMBO molecular medicine
Yang HW, Yang D, Dai H, Zhang Y, Zhao S, Zhang S, Ma Y, Wang G, Zheng S, Carroll RS, Johnson MD. (2021). Deletions in CWH43 cause idiopathic normal pressure hydrocephalus. Radiology Publications. https://doi.org/10.15252/emmm.202013249. Retrieved from https://escholarship.umassmed.edu/radiology_pubs/585
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This work is licensed under a Creative Commons Attribution 4.0 License.