The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.
Histone variants expand chromatin functions in eukaryote genomes. H2A.B genes are testis-expressed short histone H2A variants that arose in placental mammals. Their biological functions remain largely unknown. To investigate their function, we generated a knockout (KO) model that disrupts all 3 H2A.B genes in mice. We show that H2A.B KO males have globally altered chromatin structure in postmeiotic germ cells. Yet, they do not show impaired spermatogenesis or testis function. Instead, we find that H2A.B plays a crucial role postfertilization. Crosses between H2A.B KO males and females yield embryos with lower viability and reduced size. Using a series of genetic crosses that separate parental and zygotic contributions, we show that the H2A.B status of both the father and mother, but not of the zygote, affects embryonic viability and growth during gestation. We conclude that H2A.B is a novel parental-effect gene, establishing a role for short H2A histone variants in mammalian development. We posit that parental antagonism over embryonic growth drove the origin and ongoing diversification of short histone H2A variants in placental mammals.
1The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the 2 synaptic vesicle (SV) protein CSPα, which is a critical co-chaperone of Hsc70 protecting synapses from 3 activity-dependent degeneration. We developed the first animal models of CLN4 by expressing either 4 CLN4 mutant human CSPα (hCSPα) or Drosophila CSP (dCSP) in fly neurons. Similar to patients, CLN4 5 mutations induced excessive oligomerization of mutant hCSPα and premature lethality in a dose-6 dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα abnormally 7 accumulated in axons and somata, and co-localized with ubiquitinated proteins and the prelysosomal 8 markers HRS and LAMP1. Ultrastructurally, abnormal multi-laminar membrane structures were 9 frequently observed in axons and somata next to degenerative abnormalities. The lethality, 10 oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing 11 wild type (WT) dCSP levels and enhanced by increasing WT dCSP or hCSPα levels, which indicates that 12 both CLN4 alleles resemble dominant hypermorphic gain of function mutations. Furthermore, reducing 13
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