• keratosis follicularis

This report describes a model of Darier-White disease (DAR), also known as keratosis follicularis, an autosomal dominant skin disorder. The human gene implicated in this disease is ATP2A2, a SERCA Ca(2+)-ATPase; members of this family function as intracellular pumps located in the sarcoplasmic or endoplasmic reticulum. There is a single orthologous gene in Drosophila, Dmel\SERCA, for which classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\SERCA is also orthologous to ATP2A1 and ATP2A3; see the human disease model report for 'neuromuscular disease, ATP2A-related' (FBhh0000729).

The human ATP2A2 gene has not been introduced into flies.

Several mutations isolated in flies as alleles of SERCA, based on the temperature-sensitive uncoordinated phenotype of mutations of that gene, were subsequently determined to affect conserved amino acids with analogous variants implicated in Darier-White disease; an additional variant implicated in Darier-White disease was introduced in a transgenic construct. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R751Q in the fly SERCA gene (corresponds to R750Q in the human ATP2A2 gene), E412K in the fly SERCA gene (corresponds to E412K in the human ATP2A2 gene), R131H in the fly SERCA gene (corresponds to R131Q, R131L in the human ATP2A2 gene), M494L in the fly SERCA gene (corresponds to M494L, M494I in the human ATP2A2 gene).

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.

[updated Jan 2020 by FlyBase; FBrf0222196]