Abstract
Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.
Highlights
Cerebral dysgenesis, or abnormal development of the telencephalon, encompasses a large number of malformations of cortical development including cortical dysplasia, microcephaly, heterotopia, schizencephaly, and polymicrogyria [1]
We identified a pathogenic variant in domestic cats that likely causes failure of the cerebral cortex to expand and fold properly, and discovered that the pathogenic variant impairs production of a protein, PEA15, involved in intracellular signaling
PEA15 mutation and lissencephaly in the domestic cat storage diseases, and in which pathogenic variants are segregating for GM2 gangliosidosis variant AB (GM2A) [11], and mucopolysaccharidosis VI (MPSVI) [12]
Summary
Abnormal development of the telencephalon, encompasses a large number of malformations of cortical development including cortical dysplasia, microcephaly, heterotopia, schizencephaly, and polymicrogyria [1]. Mendelian causes of cerebral dysgenesis in humans includes loss of function variants in WDR62, NDE1, DYNC1H1, KIF5C, KIF2A, and TUBG1 and related genes [3]. The few studies that do exist in gyrencephalic models provide important insights into mechanisms of gyrification [7, 8], and gyrification studies are being conducted in relevant gyrencephalic species such as cats, sheep, and dogs [4]. Cats have prominent gyrification and are commonly used as a model for numerous neurologic diseases [9, 10]
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