UMMS Affiliation

Department of Neurological Surgery; Department of Radiology

Publication Date

2021-01-18

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology | Neurosurgery

Abstract

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.

Keywords

CWH43, GPI-anchored protein, hydrocephalus, normal pressure hydrocephalus

Rights and Permissions

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

10.15252/emmm.202013249

Source

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

Journal/Book/Conference Title

EMBO molecular medicine

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33459505

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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