Functional characterization of the CRY2 circadian clock component variant p.Ser420Phe revealed a new degradation pathway for CRY2

A rare CRY2 variant, p.Ser420Phe, is associated with a 7-hour shorter circadian period length.

• p.Ser420Phe CRY2 has reduced ability to repress CLOCK:BMAL1-driven transcription.
• This variant shows lower affinity to the core clock protein PER2 and impaired nuclear translocation.
• It exhibits resistance to degradation through the canonical proteasomal pathway due to loss of interactions with E3 ligases.
• Both wild-type and CRY2 variants are degraded via a lysosomal-mediated degradation pathway, a novel finding for CRY2.
• The p.Ser420Phe variant contrasts with observations in CRY2 cell lines, leading to a shorter circadian rhythm period.

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