1. Deletions in CWH43 cause idiopathic normal pressure hydrocephalus.
- Author
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Yang, Hong Wei, Lee, Semin, Yang, Dejun, Dai, Huijun, Zhang, Yan, Han, Lei, Zhao, Sijun, Zhang, Shuo, Ma, Yan, Johnson, Marciana F, Rattray, Anna K, Johnson, Tatyana A, Wang, George, Zheng, Shaokuan, Carroll, Rona S, Park, Peter J, and Johnson, Mark D
- 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. Synopsis: Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging characterized by enlarged cerebral ventricles, gait and balance difficulty, incontinence and cognitive impairment. The cause of iNPH is not known. Whole exome sequencing identified heterozygous damaging deletions in CWH43 in 15% of iNPH patients, and these deletions were statistically enriched when compared to the general population.Mutant Cwh43 proteins fail to localize to the Golgi apparatus, which is where Cwh43 normally modifies the lipid anchor of glycosylphosphatidylinositol (GPI)‐anchored proteins.Certain GPI‐anchored proteins (e.g. CD59) were no longer associated with lipid microdomains in human and mouse cells harboring iNPH‐associated CWH43 deletions.Mice heterozygous or homozygous for CWH43 deletions displayed enlarged ventricles, gait and balance abnormalities, decreased cilia numbers and decreased expression of GPI‐anchored proteins on the apical surfaces of choroid plexus and ependymal cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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