Deletions in CWH43 cause idiopathic normal pressure hydrocephalus

EMBO Molecular Medicine

Marciana F Johnson¹  Lei Han¹  Peter J Park¹  Semin Lee¹  Tatyana A Johnson¹  Anna K Rattray¹  Shuo Zhang²  George Wang²  Mark D Johnson²  Yan Ma²  Dejun Yang²  Rona S Carroll²  Hong Wei Yang²  Huijun Dai²  Sijun Zhao²  Yan Zhang²  Shaokuan Zheng² 

[1] Brigham and Women’s Hospital Boston MA USA;University of Massachusetts Medical School Worcester MA USA;

关键词: CWH43;    GPI‐anchored protein;    hydrocephalus;    normal pressure hydrocephalus;   

DOI  :  10.15252/emmm.202013249

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown