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Sifrim-Hitz-Weiss syndrome

Publications on Sifrim-Hitz-Weiss syndrome

Human Molecular Genetics (Dec 15, 2023) Divergent phenotypes in constitutive versus conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome

Larrigan S, Joshi SV, Mattar P

DOI: 10.1093/hmg/ddad157 >>

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This study describes phenotypic differences between constitutive and conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome, an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. Behavioral and organic deficits depended on the location and timing of the loss-of-function mutation of CHD4, resulting in unexpected phenotypic divergence. Behavioral tests characterized the deficits of these mice. As many of these tests were vision-based, Larrigan et al used the OptoDrum to establish that these mice did not have any obvious visual deficits.

Chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES)-an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain-either constitutively, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited no change in cortical size and cellular composition and had only subtle behavioral phenotypes. Telencephalon-specific conditional knockouts had marked reductions in cortical growth, reduced numbers of upper-layer neurons, and exhibited alterations in anxiety and repetitive behaviors. Despite the fact that whole-body heterozygotes exhibited comparable growth defects, they were unaffected in these behaviors, but instead exhibited female-specific alterations in learning and memory. These data reveal unexpected phenotypic divergence arising from differences in the spatiotemporal deployment of loss-of-function manipulations, underscoring the importance of context in chromatin remodeller function during neurodevelopment.