<i>CACNA1D</i> is a circadian gene and causes familial advanced sleep phase.

Webb, John M; Abderemane-Ali, Fayal; Ashbrook, Liza; Ma, Mingyang; Nibber, Neha; Zou, Xianlin; Yamazaki, Maya; Wohler, Elizabeth et al. · Proc Natl Acad Sci U S A · 2025

basic_science · Level V

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Abstract

Familial advanced sleep phase (FASP) is a heritable human sleep trait characterized by early sleep onset and offset times. We have identified five variants in five different families in the human voltage-gated calcium channel subunit alpha1 D (<i>CACNA1D</i>) that cosegregate with FASP. The variants in <i>CACNA1D</i> lead to altered channel dynamics in vitro. A mouse model of the E427K variant has a normal circadian period under constant darkness but displays altered phase shifts in response to light in the subjective night at circadian time (CT) 16 and CT22. Overall, these experiments establish <i>CACNA1D</i> as an FASP gene with altered entrainment, highlighting the ability of human genetics to uncover novel aspects of human circadian regulation.

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