In affected members of a large 3-generation Indian family (family 1) with idiopathic generalized epilepsy (EIG8; 612899), Kapoor et al. (2008) identified a heterozygous c.2693G-A transition (c.2693G-A, NM_000388) in the CASR gene, resulting in an arg898-to-gln (R898Q) substitution at a highly conserved residue located close to 3 potential phosphorylation sites. The mutation segregated with the disorder in the family and was not detected in 504 control chromosomes. Seizure types in this family were variable, but included myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. None of the patients had electrolyte abnormalities. Four additional possibly pathogenic variants in the CASR gene were identified in 5 of 96 unrelated patients with juvenile myoclonic epilepsy from southern India.
Stepanchick et al. (2010) found that the R898Q mutation resulted in extracellular calcium-stimulated ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation levels equal to or greater than those of wildtype CASR, suggesting that this mutation induces a gain-of-function phenotype.
