• nemaline myopathy 7

This report describes nemaline myopathy 7 (NEM7), a subtype of nemaline myopathy; NEM7 exhibits autosomal recessive inheritance. The human gene implicated in this disease is CFL2, which encodes a protein involved in the regulation of actin polymerization and depolymerization. The highest-scoring ortholog in Drosophila is tsr, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are additional homologous genes in both human (CFL1 and DSTN) and flies (CG6873).

UAS constructs of the human Hsap\CFL2 gene have been introduced into flies, including wild-type and a variant implicated in NEM7. A UAS construct of the wild-type Hsap\CFL1 gene has also been introduced into flies. Heterologous rescue (functional complementation) is observed: both wild-type human genes improve larval mobility of animals with muscle-specific knockdown of Dmel\tsr.

Variant(s) implicated in human disease tested (as transgenic human gene, CFL2): the V7M variant variant of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene: V7M in the fly tsr gene (corresponds to the V7M in the human CFL2 gene). This variant also improves larval mobility of animals with muscle-specific knockdown of Dmel\tsr, but to a lesser extent than wild-type Hsap\CFL2 or Hsap\CFL1. It is postulated to be a partial loss-of-function mutation.

Animals homozygous for loss-of-function mutations of Dmel\tsr typically die in the larval stage. Muscle-specific knockdown in embryos and larvae, effected by RNAi, results in little change up to the end of embryogenesis; during larval stages disruption of sarcomere structure and progressive deterioration of muscle function are observed.

[updated Aug. 2020 by FlyBase; FBrf0222196]