Alleic variants of human melatonin 1a receptor: Function and prevalence insubjects with circadian rhythm sleep disorders

The human melatonin la (hMella) receptor gene was screened for mutations us ing genomic DNA samples from patients with circadian rhythm sleep disorders and control subjects by single strand conformational polymorphism analysis (SSCP). We found seven mutations, two of which predict amino acid changes R54W and A157V, respectively. The prevalence of the R54W variant and that o f the A157V variant were several times more common in non-24-h sleep-wake s yndrome subjects than among control subjects, although the incidence was no t significant in our study group. When expressed in COS-7 cells, the R54W m utant receptor exhibited significantly reduced B-max and slightly enhanced affinity (reduced K-d) compared to the wild type receptor, while the A157V variant receptor showed similar binding characteristics to the wild type. T he identification of variants in the hMella receptor will provide a useful tool for analyzing genetic predisposition toward various diseases related t o melatonin function and to clarify the physiological role of melatonin rec eptors in humans. (C) 1999 Academic Press.