PEA15loss of function and defective cerebral development in the domestic cat

Abstract

26Cerebral cortical size and organization are critical features of neurodevelopment and human 27 evolution, for which genetic investigation in model organisms can provide insight into 28 developmental mechanisms and the causes of cerebral malformations. However, some 29 abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory 30 mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in 31 domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a 32 smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in 33 PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 34 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, 35 present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral 36 defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% 37 average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian 38 and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is 39 substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the 40 cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. 41Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and 42 increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an 43 intracellular adapter protein, and suggesting an underlying pathophysiology in which increased 44 death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal 45 organization of neuronal layers and loss of white matter. Taken together, our work points to a new 46 role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic 47 species. 48 49 Summary 51Gyrification is the neurodevelopmental process in certain mammalian species during which the 52 cerebral cortex expands and folds resulting in the classic wrinkled appearance of the brain. 53Abnormalities in this process underlie many congenital malformations of the brain. However, 54 unlike many other human malformations, genetic insight into gyrification is not possible in 55 laboratory mice because rodents have a lissencephalic or smooth cerebral cortex. We identified 56 a mutation in domestic cats that likely causes failure of the cerebral cortex to expand and fold 57properly, and discovered that the mutation impairs production of a protein, PEA15 58(phosphoprotein expressed in astrocytes-15), involved in intracellular signaling. Affected cats 59 have profound abnormalities in brain development, with minimal changes in their superficial 60 behavior and neurologic function. Additional studies of tissue and cultured cells from affected 61 animals suggest a pathophysiologic mechani...

Accurate analysis of short read sequencing in complex genomes: A case study using QTL-seq to target blanchability in peanut (Arachis hypogaea)

“…Khufu also is effective for mapping traits in domestic cats. Graff et al (2020) identified a mutation in PEA15 that leads to impaired cerebral cortical size in domestic cats by analyzing sequence data from a set of affected and unaffected individuals. We analyzed only the WGS data which included 3 obligate carriers and 2 affected cats and RNA-seq data including 7 affected cats and 4 unaffected cats (Figure S11).…”

Cats – telomere to telomere and nose to tail

“…Whole genome sequencing (WGS) and whole exome sequencing (WES) are available for domestic cats as genomic diagnostic tools for their healthcare via the community-based 99 Lives Cat Genome Sequencing Consortium [4,5]. Consortium studies are defining new disease variants for well-recognized disease genes, thereby supporting established biomedical models, such as Niemann-Pick disease type C [6]; new variants in new genes for known diseases, such as disproportionate dwarfism, thereby providing new genetic considerations for undiagnosed patients [7]; and new variants for new diseases of conserved biological processes, such as brain development or cell migration and differentiation [8]. The cat's genomic tools and the 99 Lives Consortium have led to more rapid identification of causal disease and trait variants in cats, hence naturally occurring biomedical models, with~84 mutations causing diseases under negative selection and 44 desired variants under positive selection in cats and at least seven variants influencing one blood group (https://omia.…”

Precision medicine in cats—The right biomedical model may not be the mouse!

“…Genome editing of induced pluripotent stems cells supports VUS studies by creating the “disease in a dish” [ 5 , 6 ]; however, information from other species, comparative genetics, remains an invaluable tool to decipher VUS physiological effects, thereby influencing their priority for investigation. The research by Graff and colleagues, “ PEA15 loss of function and defective cerebral development in the domestic cat , ” is a strong example of when the murine model just does not rise to the challenge [ 7 ], and the value of other species models is recognized.…”

“…Based on the analysis of primary astrocyte cultures from knockout mice, phosphoprotein expressed in astrocytes-15 ( Pea15) has been known for decades to be expressed in astrocytes and normally functions to suppress tumor necrosis factor alpha (Tnfα)-induced apoptosis in these cells [ 8 ]. However, mice with Pea15- targeted mutations have normal brain size and morphology, contrary to a newly defined neurological model in domestic cats [ 7 , 9 ]. Thus, PEA15 was not strongly implicated in brain development.…”