ClinVar

In affected members of a large multigenerational family (family 50025) with familial natural short sleep-2 (FNSS2; 618591), Shi et al. (2019) identified a heterozygous C-to-T transition in the ADRB1 gene, resulting in an ala187-to-val (A187V) substitution at a highly conserved residue in the fourth transmembrane domain. The variant, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the phenotype in the family. It was found at a low frequency in the ExAC database (4.028 of 100,000 alleles). In vitro functional expression studies in HEK293 cells showed that the variant protein was less stable and was associated with decreased cAMP production in response to stimulation compared to wildtype. Mice with a heterozygous A187V mutation generated using CRISPR/Cas9 techniques demonstrated a short sleep phenotype, with increased mobile time during both the light and dark phases. Mice carrying the variant had about 55 minutes shorter total sleep time compared to wildtype mice, which affected both non-REM and REM sleep. Detailed studies in mice showed high expression of the ADRB1 gene in the dorsal pons within neurons that showed altered activity throughout the sleep cycle. ADRB1+ cells, which were primarily glutamatergic or GABAergic, were 'wake promoting.' Electrophysiologic properties and activity of the Adrb1+ neurons were altered by the A187V variant, with an overall increase in Adrb1+ neuron population activity and increased excitability. The variant showed a dominant effect. The findings suggested a role for ADRB1 receptors in regulation of the sleep/wake cycle.