Based on studies of a 3-generation pedigree, it has been postulated that the WDFY3 gene is implicated in a form of autosomal dominant microcephaly (MCPH18). WDFY3 encodes a scaffold protein which complexes with other autophagic components to effect macroautophagy-mediated clearance of aggregated intracellular proteins. There is a single orthologous gene in Drosophila, bchs, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\bchs is less closely related to a second human gene, WDFY4.
Several UAS constructs carrying the C-terminal portion of the human Hsap\WDFY3 gene have been introduced into flies. For the assays used, ubiquitous expression of the wild-type version of the WDFY3 C-terminal produces no abnormal phenotype, however, expression of a comparable construct carrying the putative pathological variant results in lethality at the pupal stage. Pupae carrying the WDFY3 variant had multiple anatomical defects of the brain, including smaller volume; despite ubiquitous expression, only neuronal tissues appear abnormal.
Variant(s) implicated in human disease tested (as transgenic human gene, WDFY3): the R2637W variant form has been introduced into flies; in context of the C-terminal portion of the WDFY3 protein (terminal 1226aa).
Animals homozygous for loss-of-function alleles of Dmel\bchs survive to adulthood, but have a shortened adult life-span; age-dependent ubiquitinated aggregates are observed throughout the CNS; mutant brains exhibit an elevation in total ceramide levels. The role of sphingolipid/ceramide metabolism has been investigated in this system: it is postulated that a shift of sphingolipid metabolism from de novo pathways to salvage pathways ameliorates neural degeneration, in part by improving autophagic clearance.
Extensive genetic interactions have been described for Dmel\bchs; see the bchs gene report.
[updated Mar. 2019 by FlyBase; FBrf0222196]
Primary microcephaly (MCPH) refers to the clinical finding of a head circumference less than 3 standard deviations below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation; additional clinical features may include short stature or mild seizures (review by Woods et al., 2005; pubmed:15806441). [from MIM:251200; 2016.06.16]
[MICROCEPHALY 18, PRIMARY, AUTOSOMAL DOMINANT; MCPH18](https://omim.org/entry/617520)
[WD REPEAT- AND FYVE DOMAIN-CONTAINING PROTEIN 3; WDFY3](https://omim.org/entry/617485)
In a 3-generation family multiple individuals had microcephaly with mild to moderate intellectual disability. None had apparent dysmorphic features or ocular malformations. Brain imaging showed no structural defects (Kadir et al., 2016; pubmed:27008544). [from MIM:617520; 2017.09.11]
There is evidence from one family that autosomal dominant primary microcephaly 18 (MCPH18) is caused by heterozygous mutation in the WDFY3 gene. [from MIM:617520; 2017.09.11]
WDFY3 encodes a phosphatidylinositol 3-phosphate-binding protein that functions as a master conductor for aggregate clearance by autophagy. This protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of the aggregated proteins. [Gene Cards, WDFY3; 2017.09.12]
Many to one: 2 human to 1 Drosophila.
High-scoring ortholog of human gene WDFY3; moderate-scoring ortholog of WDFY4 (1 Drosophila to 2 human). Dmel\bchs shares 47% identity and 63% similarity with the human WDFY3 gene.
