The mutation of Pro(789) to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease

Brody disease is a rare inherited disorder of fast-twitch skeletal muscle f unction and is characterized by a lifelong history of exercise-induced impa irment of skeletal muscle relaxation, stiffness, and cramps. The autosomal recessive inheritance of mutations in ATP2A1, the gene encoding SERCA1, whi ch is the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, h as been associated with Brody disease in three of six Brody families in whi ch ATP2A1 has been sequenced. In the present analysis of the ATP2A1 gene in four unrelated families with autosomal recessive inheritance of Brody dise ase, three mutations were found in two families, leading to premature stop codons and truncated SERCA1. In a third family, the homozygous substitution of T for C2366 led to the missense mutation of Pro(789) to Leu. The Pro(78 9) to Leu mutant was readily expressed in HEK-293 cells, but it demonstrate d an almost complete loss of Ca2+ transport activity because of reduced Ca2 + affinity. In a fourth family, the heterozygous substitution of T for C345 5, mutating Arg(819) to CYs, was identified. This mutation was also readily expressed in HEK-293 cells and shown to have near normal Ca2+ transport ac tivity, indicating that it is not causal for Brody disease. These results c onfirm the genetic heterogeneity of Brody disease and emphasize the importa nce of a functional test for mutant SERCA1; immunostaining of skeletal musc le to detect the loss of SERCA1a protein is not adequate for the diagnosis of ATP2A1-linked Brody disease.