This report describes neurodegenerative disease, PNPLA6-related, which includes several neurological/hormonal disorders caused by the gene PNPLA6. PNPLA6 encodes a phospholipase that deacetylates intracellular phosphatidylcholine. There is a single fly ortholog, sws, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\sws is also orthologous to a second human gene, PNPLA7.
Diseases associated with PNPLA6 include Boucher-Neuhauser syndrome (FBhh0000388, MIM:215470), Oliver-McFarlane syndrome (FBhh0000389, MIM:275400), and spastic paraplegia 39 (FBhh0000367, MIM:612020). Work in flies also implicates this gene in Leber congenital amaurosis or a similar disease (FBhh0000391).
Multiple UAS construct of the human Hsap\PNPLA6 gene has been introduced into flies, including wild-type and genes carrying mutational lesions. Partial heterologous rescue (functional complementation) of Dmel\sws CNS phenotypes has been demonstrated. Multiple variants implicated in (or postulated to be implicated in) the PNPLA6 disease spectrum have been characterized in flies. Variant(s) implicated in human disease tested (as transgenic human gene, PNPLA6): the S1175C (S1127C), D424 (D376) frameshift, R1147C (R1099C), L524P (L476P), G578W (G530W), R1099Q (R1051Q), T629R (T581R), and A1029T (A981T) variants have been introduced into flies. Many of these variants are implicated in Boucher-Neuhauser syndrome (see FBhh0000388).
Loss-of-function alleles of Dmel\sws result in progressive neuroanatomy defective phenotypes, including in the adult eye and the adult brain; lifespan is shortened. Loss of expression in glia, as well as in neurons, results in neuronal defects. Genetic interactions of the Dmel\sws protein product have been described; see the sws gene report.
[updated Mar. 2020 by FlyBase; FBrf0222196]
PNPLA6-related disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia, upper motor neuron involvement manifesting as spasticity and/or brisk reflexes, chorioretinal dystrophy associated with variable degrees of reduced visual function, anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies), and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). [from Gene Reviews, PNPLA6-Related Disorders; 2016.08.15]
PNPLA6 encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. This protein is the target for neurodegeneration induced by certain organophosphorus compounds and chemical warfare agents. [Gene cards, PNPLA6; 2016.08.16]
Many to one (2 human to 1 Drosophila); the second orthologous gene in human is PNPLA7.
High-scoring ortholog of human PNPLA6 and PNPLA7 (1 Drosophila to 2 human). Dmel\sws shares 42% identity and 59-60% similarity with the human genes.
