| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q25.3 | [Short sleep, familial natural, 2] | 618591 | Autosomal dominant | 3 | ADRB1 | 109630 |
A number sign (#) is used with this entry because of evidence that familial natural short sleep-2 (FNSS2) is caused by heterozygous mutation in the ADRB1 gene (109630) on chromosome 10q24. One such family has been reported.
Individuals with familial natural short sleep-2 (FNSS2) have a sleep requirement of 4 to 6 hours per night (Shi et al., 2019).
For a discussion of genetic heterogeneity of FNSS, see FNSS1 (612975).
Shi et al. (2019) reported a 5-generation family (kindred 50025) in which at least 6 individuals had short sleep. On average, affected individuals slept for 5.7 hours per night, compared to unaffected individuals who slept 7.9 hours per night.
The transmission pattern of FNSS2 in the family reported by Shi et al. (2019) was consistent with autosomal dominant inheritance. There was evidence of variable expressivity.
In affected members of a large multigenerational family with FNSS2, Shi et al. (2019) identified a heterozygous missense mutation in the ADRB1 gene (A187V; 109630.0003). 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.
Shi, G., Xing, L., Wu, D., Bhattacharyya, B. J., Jones, C. R., McMahon, T., Chong, S. Y. C., Chen, J. A., Coppola, G., Geschwind, D., Krystal, A., Ptacek, L. J., Fu, Y.-H. A rare mutation of beta-1-adrenergic receptor affects sleep/wake behaviors. Neuron 103: 1044-1055, 2019. [PubMed: 31473062] [Full Text: https://doi.org/10.1016/j.neuron.2019.07.026]