Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities

Abstract

ObjectiveTo identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH.MethodsWe performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene. Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus.ResultsIn WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 encoding cilia- and flagella-associated protein is preferentially expressed in the testis. Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia.ConclusionOur results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.

Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization

“…With advances in sequencing and improvements in variant interpretation techniques, the tremendous heterogeneity of neurogenetic disorders is more evident and it is increasingly apparent that genes once associated only with one form of inheritance are in fact capable of causing both recessive and dominant forms. [24][25][26][27] The nomenclature that assigns a sequential number to each gene in a disease category provides no clarifying information and has limited clinical or research utility. As proposed, regarding the nomenclature of recessive cerebellar ataxia 28 and other genetic movement disorders, 29 we suggest ATX-STUB1 and SCA-STUB1 to replace SCAR16 and SCA48.…”

CFAP43 modulates ciliary beating in mouse and Xenopus

“…Ependymal cilia were motile both in mouse and frog, and ependymal flow in mouse brains was apparently unaltered. Recently, a heterozygous mutation in Cfap43 was described in a Japanese family with normal pressure hydrocephalus (NPH) (Morimoto et al, 2019). NPH constitutes a variant of hydrocephalus that develops past the age of 40 and is characterized by excess cerebrospinal fluid production.…”

“…In-depth studies, beyond the scope of the present investigation, are needed to unravel the molecular mechanism of hydrocephalus formation in mutant mice. It is tempting to speculate, however, that a choroid plexus ciliary defect results in excess CF, which causes early onset hydrocephalus in mouse and NPH in humans, although the presumed dominant-negative mode of action of the described human mutation (Morimoto et al, 2019) needs to be confirmed and mechanistically evaluated. The lack of hydrocephalus in mutant frog embryos may be due to the much earlier time point of analysis, before the onset of metamorphosis.…”

“…We identified Cfap43 in microarray screens for genes that were up-regulated during the differentiation of ciliated cells in the fetal mouse lung and down-regulated in Foxj1 mutants (Stauber et al, 2017). Patients heterozygous for a truncated CFAP43 protein were reported to develop normal pressure hydrocephalus (Morimoto et al, 2019), and homozygous missense and nonsense mutations in CFAP43 were identified in sterile male patients with 'multiple morphological abnormalities of the sperm flagella' (MMAF (Coutton et al, 2018;Sha et al, 2017;Tang et al, 2017)). Other symptoms related to non-functional motile cilia were not reported from such patients.…”

This was the year that was: brain barriers and brain fluid research in 2019

“…Cilia defects have been implicated in hydrocephalus pathology for some time and primary ciliopathies affect various aspects of brain development, including hydrocephalus [133]. For example, Morimoto et al [134] identified a loss of function mutation in CFAP3, a cilia-associated protein, in a Japanese family where some members have NPH. In addition, they found that Cfap3-deficient mice also develop hydrocephalus.…”