• dilated cardiomyopathy

Two forms of dilated cardiomyopathy are associated with presenilin genes in human: PSEN1 is implicated in dilated cardiomyopathy 1U (CMD1U, FBhh0000154) and PSEN2 is implicated in dilated cardiomyopathy 1V (CMD1V, FBhh0000155). Both CMD1U and CMD1V exhibit autosomal dominant inheritance. Presenilin is the catalytic component of a gamma-secretase complex. Gamma-secretase is a multiprotein complex containing PSEN1 or PSEN2 and multiple other components; it is responsible for proteolytic cleavage of amyloid precursor protein (APP) and NOTCH receptor proteins. There is a single presenilin in Drosophila, Dmel\Psn, for which classical hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Multiple different UAS constructs of both human genes, Hsap\PSEN1 and Hsap\PSEN2 have been introduced into flies, including wild-type and genes carrying mutational lesions implicated in Alzheimer disease. Human variants implicated in cardiomyopathy have not been characterized in the fly system.

In flies, it appears that levels of expression of Dmel\Psn need to be within a precise range: homozygous loss-of-function mutations in the Dmel\Psn gene are lethal; loss of function effected by RNAi in mesodermal tissues leads to a significantly reduced heart rate in adults, irregular heartbeat rhythms, cardiomyofibril defects, and mitochondrial impairment; overexpression also results in cardiac phenotypes. Physical and genetic interaction(s) of the Dmel\Psn protein product have been described; see below and in the FlyBase gene report for Psn.

For transgenic human constructs, fly transgenic constructs and classical alleles, detailed phenotypic descriptions can be found in the allele reports; allele reports can be accessed from the gene report or by clicking on the allele symbols in the Disease Ontology and Reagent tables below.

[updated Mar. 2018 by FlyBase; FBrf0222196]