TY - JOUR
T1 - The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease
AU - Odermatt, Alex
AU - Barton, Kimby
AU - Khanna, Vijay K.
AU - Mathieu, Jean
AU - Escolar, Diana
AU - Kuntzer, Thierry
AU - Karpati, George
AU - MacLennan, David H.
N1 - Funding Information:
Acknowledgements This study would not have been possible without the invaluable cooperation of family members and collaborating physicians. This research was supported by grants to D.H.M. from the Muscular Dystrophy Association (USA), the Muscular Dystrophy Association (Canada), the Canadian Genetic Diseases Network of Centers of Excellence, and the Medical Research Council of Canada (grant MT-12545). K.B. is the recipient of a studentship from the Medical Research Council of Canada.
PY - 2000
Y1 - 2000
N2 - Brody disease is a rare inherited disorder of fast-twitch skeletal muscle function and is characterized by a lifelong history of exercise-induced impairment of skeletal muscle relaxation, stiffness, and cramps. The autosomal recessive inheritance of mutations in ATP2A1, the gene encoding SERCA1, which is the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, has been associated with Brody disease in three of six Brody families in which ATP2A1 has been sequenced. In the present analysis of the ATP2A1 gene in four unrelated families with autosomal recessive inheritance of Brody disease, 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 Pro789 to Leu. The Pro789 to Leu mutant was readily expressed in HEK-293 cells, but it demonstrated an almost complete loss of Ca2+ transport activity because of reduced Ca2+ affinity. In a fourth family, the heterozygous substitution of T for C2455, mutating Arg819 to Cys, was identified. This mutation was also readily expressed in HEK-293 cells and shown to have near normal Ca2+ transport activity, indicating that it is not causal for Brody disease. These results confirm the genetic heterogeneity of Brody disease and emphasize the importance of a functional test for mutant SERCA1; immunostaining of skeletal muscle to detect the loss of SERCA1a protein is not adequate for the diagnosis of ATP2A1-linked Brody disease.
AB - Brody disease is a rare inherited disorder of fast-twitch skeletal muscle function and is characterized by a lifelong history of exercise-induced impairment of skeletal muscle relaxation, stiffness, and cramps. The autosomal recessive inheritance of mutations in ATP2A1, the gene encoding SERCA1, which is the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, has been associated with Brody disease in three of six Brody families in which ATP2A1 has been sequenced. In the present analysis of the ATP2A1 gene in four unrelated families with autosomal recessive inheritance of Brody disease, 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 Pro789 to Leu. The Pro789 to Leu mutant was readily expressed in HEK-293 cells, but it demonstrated an almost complete loss of Ca2+ transport activity because of reduced Ca2+ affinity. In a fourth family, the heterozygous substitution of T for C2455, mutating Arg819 to Cys, was identified. This mutation was also readily expressed in HEK-293 cells and shown to have near normal Ca2+ transport activity, indicating that it is not causal for Brody disease. These results confirm the genetic heterogeneity of Brody disease and emphasize the importance of a functional test for mutant SERCA1; immunostaining of skeletal muscle to detect the loss of SERCA1a protein is not adequate for the diagnosis of ATP2A1-linked Brody disease.
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U2 - 10.1007/s004390000297
DO - 10.1007/s004390000297
M3 - Article
C2 - 10914677
AN - SCOPUS:0033623915
SN - 0340-6717
VL - 106
SP - 482
EP - 491
JO - Human genetics
JF - Human genetics
IS - 5
ER -