• neuromuscular disease

A dominant mutation of Dmel\SERCA has been identified that causes an uncoordinated phenotype; the mutation is temperature-sensitive. Dmel\SERCA encodes an ATPase sarcoplasmic/endoplasmic reticulum Ca[2+] transporting protein; it is orthologous to three genes in human, ATP2A1, ATP2A2, and ATP2A3. ATP2A1 and ATP2A2 are implicated in human diseases (see Brody myopathy, MIM:601003, and the OMIM report for ATP2A2, MIM:108740), as are several related genes (see 'neurological disorders, ATPα-related' FBhh0000547, and 'migraine, familial hemiplegic 2' FBhh0000548). Classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\SERCA.

None of the ATP2A human genes has been introduced into flies.

While ubiquitous RNAi knockout is generally lethal, some tissue-specific knockouts are viable. For example, flies with SERCA knocked down in undifferentiated muscle precursors (twi driver) and in muscle fibers (Mhc driver) show abnormalities in large thoracic muscles such as myofibrillar disorganization, loss of striation and/or nuclei, and decreased locomotor activity.

A number of Dmel\SERCA mutations exhibit a recessive lethal phenotype and dominant heat-sensitive uncoordinated or paralytic phenotype. Most mapped mutations in this class affect amino acids conserved across P-type ATPase genes. In a number of cases, the affected amino acids correspond to variants implicated in human disease (in different human P-type ATPase genes); the majority of these correspond to variants in the ATP2A2 gene implicated in a severe skin disorder, Darier-White disease (FBhh0000730).

Experiments in flies support a disease model invoking a gain-of-function mechanism of ionic leakage, rather than a loss-of-function that results in haploinsufficiency. Genetic and many physical interactions have been described for Dmel\SERCA; see below and in the SERCA gene report.

See also 'cardiac arrhythmia (postulated), ATP2A-related' (FBhh0000728).

[updated July 2019 by FlyBase; FBrf0222196]