Postnatal Brain Growth Patterns in Pontocerebellar Hypoplasia

et al. 2021

Preprint

Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes neurodevelopmental disorders (NDD) in girls, while in boys loss of the only allele of these genes leads to profound encephalopathy. The cellular basis for these disorders remains unknown. CASK is presumed to work through the Tbr1-reelin pathway in neuronal migration. Here we report clinical and histopathological analysis of a deceased 2-month-old boy with a CASK-null mutation. Although smaller in size, the CASK-null human brain exhibits normal lamination without defective neuronal differentiation, migration, or axonal guidance, excluding the role of reelin. The hypoplastic cerebellum instead displayed astrogliosis, a marker for neuronal loss. We therefore hypothesized that cerebellar hypoplasia with CASK loss is a result of early neurodegeneration. We generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from post-migratory neurons in the cerebellum. Data confirm that a small cerebellum in CASK-loss results from post-developmental degeneration of cerebellar granule neurons. We further demonstrate that at least in cerebellum the functional loss with CASK deletion results secondary to degeneration of granule cells rather that any acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum did not display any neurodegeneration. We suggest that NDDs like CASK mutation and Rett syndrome are pathologically neurodegenerative; however, random X-chromosome inactivation in the heterozygous mutant girls results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

Section: Introductionmentioning

confidence: 77%

“…PCH pathologies are typically thought to be neurodegenerative in their origin beginning antenatally (van Dijk et al 2020). Defects in both energy production and protein metabolism (speci cally, protein synthesis) are known to disproportionately affect the cerebellum and are likely causes of PCH (Kasher et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Complete Loss of CASK Causes Severe Ataxia Through Cerebellar Degeneration

et al. 2021

Preprint

“…PCH pathologies are typically thought to be neurodegenerative in their origin beginning antenatally 53 . Defects in both energy production and protein metabolism (specifically, protein synthesis) are known to disproportionately affect the cerebellum and are likely causes of PCH 73 .…”

Section: Discussionmentioning

confidence: 99%

“…We then design and execute a genetic experiment in mice that provides conclusive evidence that loss of CASK indeed produces neurodegeneration in the cerebellum. Most pontocerebellar hypoplasias (PCH) are progressive, but based on the postnatal brain growth pattern, it has been hypothesized that MICPCH has a distinct pathogenic mechanism 53 . We instead provide evidence that mechanistically, MICPCH in girls with heterozygous CASK mutations is also degenerative, and the non-progressive course of MICPCH is dictated by uniqueness of the X-linked inheritance pattern in which 50% of brain cells express the normal gene.…”

Section: Introductionmentioning

confidence: 99%

Complete loss of CASK causes severe ataxia through cerebellar degeneration in human and mouse

et al. 2021

Preprint

Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes neurodevelopmental disorders (NDD) in girls, while in boys such loss leads to profound encephalopathy. The cellular basis for these disorders remains unknown. CASK is presumed to work through the Tbr1-reelin pathway in neuronal migration during brain development. Here we report our clinical and histopathological analysis of a deceased 2-month-old boy with a CASK-null mutation. We demonstrate that although smaller in size, the CASK-null human brain exhibits normal lamination without defective neuronal differentiation, migration, or axonal guidance, excluding the role of reelin in CASK-linked pathology. The disproportionately hypoplastic cerebellum in humans without CASK expression is associated with cerebellar astrogliosis, a marker for neuronal loss. Cerebellum-specific deletion in mouse confirms a post-developmental degeneration of cerebellar granular neurons that results in a small cerebellum. Mechanistically, cerebellar hypoplasia in CASK mutation thus results from neurodegeneration rather that developmental defects. Zygosity-pathology correlation suggests that NDDs like CASK mutation and Rett syndrome are pathologically neurodegenerative; however, random X-chromosome inactivation in the typical heterozygous mutant girls results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

“…PCH pathologies are typically thought to be neurodegenerative in their origin beginning antenatally (53).…”

Section: Discussionmentioning

confidence: 99%

Complete loss of CASK causes severe ataxia through cerebellar degeneration

et al. 2021

Preprint

Background: Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes neurodevelopmental disorders (NDD) in girls, while in boys loss of the only allele of these genes leads to profound encephalopathy. The cellular basis for these disorders remains unknown. CASK is presumed to work through the Tbr1-reelin pathway in neuronal migration.Methods: Here we report clinical and histopathological analysis of a deceased 2-month-old boy with a CASK-null mutation. We first analyze in vivo data from the subject including genetic characterization, magnetic resonance imaging (MRI) findings, and spectral characteristics of the electroencephalogram (EEG). We next compare features of the cerebellum to an-age matched control. Based on this, we generate a murine model where CASK is completely deleted from post-migratory neurons in the cerebellum.Results: Although smaller, the CASK-null human brain exhibits normal lamination without defective neuronal differentiation, migration, or axonal guidance, excluding the role of reelin. The hypoplastic cerebellum instead displayed astrogliosis, a marker for neuronal loss. We therefore hypothesized that cerebellar hypoplasia with CASK loss is a result of early neurodegeneration. Data from our murine model confirm that a small cerebellum in the context of CASK-loss results from post-developmental degeneration of cerebellar granule neurons. We further demonstrate that at least in the cerebellum the functional loss with CASK deletion results secondary to degeneration of granule cells rather that any acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum did not display any neurodegeneration.Conclusions: Herein we demonstrate in human that complete loss of CASK is not associated with any dysfunction in the Tbr1-reelin pathway. Further, immunohistochemistry indicates a degenerative cell death which is mechanistically confirmed in our murine model. In the absence of CASK in cerebellar cells, the cerebellum develops normally but degenerates over a period of several weeks. We suggest that NDDs like CASK mutation and Rett syndrome are pathologically neurodegenerative; however, random X-chromosome inactivation in the heterozygous mutant girls results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.