Deletions in CWH43 cause idiopathic normal pressure hydrocephalus

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.

Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus

“…We previously reported that mice harboring iNPH-associated deletions in CWH43 develop communicating hydrocephalus ( Fig. 1 A ) ( 7 ). To determine whether alterations in L1CAM may contribute to this phenomenon, we examined L1CAM immunoreactivity in the ventricular and subventricular zone of the mouse brain using an antibody directed against the C terminus of L1CAM.…”

“…All experiments and procedures involving mice were approved by the University of Massachusetts Medical School Institutional Animal Care and Use Committee. C57bl6 mice harboring a Met533Ter mutation (coinciding to the human CWH43 deletion 4:49034669 CA/C; Leu533Ter) were generated using a CRISPR/Cas9 approach and bred to generate homozygous ( CWH43 M533/M533 ) animals as described previously ( 7 ). This mutation generates a stop codon that truncates the encoded Cwh43 protein and disrupts its function.…”

“…Six-month-old mice were used for MRI analysis. T2-weighted MR images of the brains of CWH43 wild-type (WT) and mutant mice were obtained, and ventricular volume was quantitated using ImageJ software ( 7 ).…”

“…Until recently, the cause of iNPH was unknown. However, we recently reported that about 15% of patients with sporadic iNPH harbor heterozygous deletions in CWH43 ( 7 ), which encodes a protein that incorporates ceramide into the lipid anchor of glycosylphosphatidylinositol (GPI)–anchored proteins ( 8 ). Mice harboring CWH43 deletions appear behaviorally normal but develop communicating hydrocephalus and gait imbalance.…”

Reappraisal of Pediatric Normal-Pressure Hydrocephalus

“…While pediatric NPH is less likely to be mentioned explicitly in the more recent literature, some of the articles published in the last decade have provided novel mechanistic insights into potential genetic and circulatory pathophysiology present in children, as well as in adults, which may contribute to the development of NPH across ages. Two pediatric articles have implicated genes pertinent to ependymal ciliary structure and function; coupled with a third recent study by Yang et al (2021) which observed a separate genetic defect also related to ependymal cilia function in 8/53 (15%) of adult idiopathic NPH patients who underwent full exosome DNA sequencing, this relatively new line of research provides insight into a potential mechanism of NPH related to cerebrospinal fluid production and circulation dynamics [ 1 , 3 , 32 ]. Separately, literature demonstrating altered cerebral blood flow dynamics in NPH supports one possible venous compensatory mechanism which may lead to ventricular dilation [ 2 , 4 , 5 , 28 ].…”