MRI of Capn15 Knockout Mice and Analysis of Capn 15 Distribution Reveal Possible Roles in Brain Development and Plasticity

Zha, Congyao; Farah, Carole A.; Fonov, Vladimir S.; Rudko, David A.; Sossin, Wayne S.

doi:10.1016/j.neuroscience.2021.04.023

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…CAPN15 binding partners have roles in the ubiquitin/proteasome pathways and in the promotion of cell division. These roles are consistent with observed properties of CAPN15 in polyubituitin binding (Hastings et al, 2018) and cell survival (Fischbach & Heisenberg, 1981;Fischbach & Technau, 1984;Zha et al, 2021) observed in animal models. known to be associated with deletions in this region (Supporting Information).…”

Section: Part Four: Capn15 Expression In Mouse Cerebellumsupporting

confidence: 89%

“…In the mouse, cerebellar progenitors are formed between E12.5 and E14.5 and continue to mature through the postnatal period (Mizuhara et al, 2010). It has previously been shown that Capn15 is enriched in the Purkinje cells of the mature cerebellum (Zha et al, 2021), though expression patterns earlier in the developmental course are unknown. We replicate this finding, and also show expression of CAPN15/SOLH in maturing Purkinje cells in early postnatal development (Figure 5), suggesting that the protein plays a role in both the developing and mature cerebellum.…”

Section: Resultsmentioning

confidence: 99%

“…The Capn15 À/À mouse has many features of oculogastrointestinal neurodevelopmental syndrome but does not have explicit cerebellar dysgenesis (Zha et al, 2020). However, by volumetric MRI evaluation, Zha et al noted a decrease in volume of the cerebellum in knockout mice (Zha et al, 2021). PCP4+ cell counting in adult knockout mice did not reveal a statistically significant decrease of Purkinje cells.…”

Section: Part Four: Capn15 Expression In Mouse Cerebellummentioning

confidence: 99%

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Novel association of Dandy–Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome

Beaman,

Guidugli,

Hammer

et al. 2023

American J of Med Genetics Pt A

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Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy–Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15‐related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy–Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy–Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15‐related disease.

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Section: Part Four: Capn15 Expression In Mouse Cerebellumsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Part Four: Capn15 Expression In Mouse Cerebellummentioning

confidence: 99%

See 1 more Smart Citation

Novel association of Dandy–Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome

Beaman,

Guidugli,

Hammer

et al. 2023

American J of Med Genetics Pt A

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“…In line with this reasoning, the noncatalytic CAPN6 has been shown to play a role in cytoskeletal stabilization and organization via its CBSW domain [70]. CAPN15 contains five N-terminal zinc fingers, suggesting that it may bind RNA or mediate protein-protein interactions (e.g., polyubiquitin; Figure 2A) [65,71,72]. These differences could be exploited in the development of isoform-specific inhibitors.…”

Section: Trends In Molecular Medicinementioning

confidence: 79%

Calpains as mechanistic drivers and therapeutic targets for ocular disease

Wang

et al. 2022

Trends in Molecular Medicine

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“…An image registration-based method was used to identify brain regions, at the voxel level, with significant local volume difference between WT and mutant mice, as described in Zha et al . 27 Briefly, a minimum deformation template was generated from the whole mouse population used in the current study, producing non-linear transformations mapping each scan into a common space. Voxel-level Jacobian determinants of the non-linear transformations were then calculated and used as a measure of the local volume difference between the average minimum deformation template and each individual mouse image.…”

Section: Methodsmentioning

confidence: 99%

Loss of symmetric cell division of apical neural progenitors drivesDENND5A-related developmental and epileptic encephalopathy

Banks

Kharfallah

Fonov

et al. 2022

Preprint

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Epileptic encephalopathies comprise a clinically and genetically heterogenous group of disorders characterized by global developmental delay and ongoing seizure activity. It is generally considered that seizure activity is the primary pathology and leads to altered cognitive function. However, epileptic encephalopathy can also result from primary defects in neurodevelopment that lead to seizures. Here we examine the symptomology of individuals with epileptic encephalopathy resulting from biallelic pathogenic variants in DENND5A, encoding a protein involved in intracellular membrane trafficking. We established a cohort of 15 individuals from 14 families with 21 unique variants in DENND5A and analyzed phenotypic surveys answered by their treating clinicians. We obtained cells derived from several cohort members and examined DENND5A expression and stability, and we examined the role of DENND5A in symmetric cell division capability. Finally, we generated a mouse line expressing a homozygous mutation found in the cohort and analyzed brain morphology in vivo using a 7 Tesla magnetic resonance imaging system. Our cohort study reveals that global developmental delay, gross abnormalities in brain development including ventriculomegaly and corpus callosum dysgenesis, seizures, microcephaly and hypotonia are found in the majority of the cohort. Patient-derived neural precursor cells from induced pluripotent stem cells, as well as patient-derived lymphoblasts, display loss of DENND5A protein and exhibit problems with symmetric cell division, an essential process in early neural development. The introduction of a homozygous human point mutation into the conserved sequence in mouse leads to an animal with reduced brain volume and widespread regional brain dysgenesis and ventriculomegaly, phenotypes shared with the human cohort. Taken together, our multi-dimensional study establishes DENND5A as a critical gene during neurodevelopment and that biallelic loss of function variants, including missense and truncating variants as well as intronic splice site variants, result in a developmental epileptic encephalopathy.

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MRI of Capn15 Knockout Mice and Analysis of Capn 15 Distribution Reveal Possible Roles in Brain Development and Plasticity

Cited by 6 publications

References 34 publications

Novel association of Dandy–Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome

Novel association of Dandy–Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome

Calpains as mechanistic drivers and therapeutic targets for ocular disease

Loss of symmetric cell division of apical neural progenitors drivesDENND5A-related developmental and epileptic encephalopathy

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