Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene

Abstract

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

Murine MPDZ ‐linked hydrocephalus is caused by hyperpermeability of the choroid plexus

“…The first reported MPDZ mutation linked to severe congenital hydrocephalus in humans would have truncated 12 of the 13 PDZ domains (Al‐Dosari et al , ). A subsequent study reported three new mutations that caused truncation of MPDZ within PDZ domain #3, a frameshift within PDZ domain #1, and a truncation within PDZ domain #5 (Saugier‐Veber et al , ). All three mutations were expected to introduce a premature stop codon and result in nonsense‐mediated decay of the transcript.…”

“…A more recent gene linked to congenital hydrocephalus is MPDZ , encoding a large modular scaffold protein that consists of 13 PDZ domains and one L27 domain (Ullmer et al , ; Adachi et al , ). Several cases of severe congenital hydrocephalus identified in five consanguineous families (Al‐Dosari et al , ; Saugier‐Veber et al , ) were linked mostly to biallelic nonsense mutations that resulted in nonsense‐mediated decay and total loss of MPDZ. A milder phenotype in a non‐consanguineous family was linked to missense mutations and a heterozygous splice site variant (Al‐Jezawi et al , ).…”

“…Two of the genetically linked congenital hydrocephalus conditions in humans were phenocopied in mice. Mice carrying loss-offunction mutations (LOF) in either L1CAM (Dahme et al, 1997;Rolf et al, 2001) or MPDZ (Feldner et al, 2017) developed severe hydrocephalus similar to human carriers of biallelic L1CAM (Kanemura et al, 2006) and MPDZ mutants (Al-Dosari et al, 2013;Saugier-Veber et al, 2017). Hydrocephalus results from impediment of the circulation of the cerebrospinal fluid (CSF), causing its accumulation in the brain ventricles as a result of either excessive CSF inflow, attenuated flow through the ventricles, or blocked outflow (Estey, 2016;Kahle et al, 2016).…”

Harnessing Omics Big Data in Nine Vertebrate Species by Genome-Wide Prioritization of Sequence Variants with the Highest Predicted Deleterious Effect on Protein Function

“…Still, variants in human MPDZ gene suggest a possible association with alcohol dependence (Karpyak et al, 2009). Variants in MPDZ have also been associated with congenital hydrocephalus, a neuropathy (Feldner et al, 2017;Saugier-Veber et al, 2017).…”

“…Their function is not yet annotated and should be investigated in the future. Saugier-Veber et al (2017) reported that MPDZ gene is a component of tight junctions, which are expressed from early brain development in choroid plexuses and ependyma.…”