NovelCASKmutations in cases with syndromic microcephaly

Abstract

Mutations in CASK cause a wide spectrum of phenotypes in humans ranging from mild X-linked intellectual disability to a severe microcephaly (MC) and pontocerebellar hypoplasia syndrome. Nevertheless, predicting pathogenicity and phenotypic consequences of novel CASK mutations through the exclusive consideration of genetic information and population-based data remains a challenge. Using whole exome sequencing, we identified four novel CASK mutations in individuals with syndromic MC. To understand the functional consequences of the different point mutations on the development of MC and cerebellar defects, we established a transient loss-of-function zebrafish model, and demonstrate recapitulation of relevant neuroanatomical phenotypes. Furthermore, we utilized in vivo complementation studies to demonstrate that the three point mutations confer a loss-of-function effect. This work endorses zebrafish as a tractable model to rapidly assess the effect of novel CASK variants on brain development.

An N‐terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy

“…This mutation has been previously reported as a LOF mutation, although the mechanism underlying the pathogenicity is not clear (Cristofoli, Devriendt, Davis, Van Esch, & Vermeesch, ). The substituted leucine in CASK's CaMK domain (Figure a) at position 209 is highly conserved in all species surveyed (Figure b), indicating that it may be a critical part of CASK's primary structure.…”

“…This mutation has been previously reported as a loss-of-function mutation, although the mechanism underlying the pathogenicity is not clear (Cristofoli, Devriendt, Davis, Van Esch, & Vermeesch, 2018). The substituted leucine in CASK’s CaMK domain (Fig.…”

“…Recently this specific mutation has been putatively shown to be pathogenic in a zebrafish model, although how the mutation affects the protein function remained unclear. Furthermore, the cause of visual impairment in the subject described in that report was not investigated (Cristofoli et al, 2018). We demonstrate that CASK L209P mutation is capable of destabilizing the protein sufficiently to produce misfolding and insolubility in a large proportion of expressed protein when transiently overexpressed.…”

Spontaneous motor-behavior abnormalities in twoDrosophilamodels of neurodevelopmental disorders

“…Stereotyped repetitive behaviors meet one of the core diagnostic criteria for autism spectrum disorder (ASD) (American Psychiatric Association, 2013), which cooccurs in a substantial minority of children with FXS (Abbeduto, McDuffie, & Thurman, 2014;Wheeler et al, 2015). While less information is available for children with CASK-related neurodevelopmental disorders (MIM #s 300422, 300749), delayed motor development and abnormal muscle tone are common, with ataxia and atypical behavior reported in some cases (Burglen et al, 2012;Cristofoli, Devriendt, Davis, Van Esch, & Vermeesch, 2018;Dunn et al, 2017;Hackett et al, 2010;Moog et al, 2011Moog et al, , 2015. Animal models of developmental brain disorders that display both cognitive deficits and relevant aberrant behaviors have strong face validity and, therefore, greater applicability for pathogenesis research and drug discovery (Nestler & Hyman, 2010).…”

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

“…Skewed X-chromosome inactivation (XCI) has shown protective effects against more severe phenotypes (Moog et al, 2011;Seto et al, 2017). Missense variants, found both in females and males cause microcephaly, XL-ID, DD or ASD (Cristofoli et al, 2018;Deciphering Developmental Disorders, 2017;Gupta et al, 2014;Hackett et al, 2010;Iossifov et al, 2014;LaConte et al, 2018;Moog et al, 2015;Piluso et al, 2009;Sanders et al, 2012;Seto et al, 2017). The molecular pathways and cellular phenotypes associated with genetic variants causing CASK-related disorders are mostly unknown, especially in human neurons.…”