Two de novo missense variants in the MYO5A gene had previously been identified in ASD probands (one proband from the Autism Sequencing Consortium in De Rubeis et al., 2014, the other from the Simons Simplex Collection in Iossifov et al., 2014). Two additional de novo missense variants in this gene were identified by whole genome sequencing in two ASD probands as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of four de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), MYO5A was determined to be an ASD candidate gene in Yuen et al., 2017.
Molecular Function
This gene is one of three myosin V heavy-chain genes, belonging to the myosin gene superfamily. Myosin V is a class of actin-based motor proteins involved in cytoplasmic vesicle transport and anchorage, spindle-pole alignment and mRNA translocation.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
The Flailer mouse was identified as a mouse model that carries a spontaneous non-homologous recombination event that results in an extra gene, named Flailer, composed by the fusion of the promoter and exons 1-2 of the Gnb5 gene fused together by a mixed intron, to exons 26-40 of the Myo5a gene. When the Flailer protein is present in a 1:1 ratio with wildtype MyosinVa it works as a dominant negative, leading to a reduced transport and abnormal synaptic clustering of receptors and scaffolding proteins such as PSD95 and AMPA receptors. In the Flailer mouse, hippocampal long-term depression is absent. The Flailer mouse also exhibits various behavioral phenotypes: increased repetitive grooming, increased anxiety, decreased contextual fear conditioning memory, and increased spontaneous seizures. A CRISPR-Cas9 construct targeted to Flailer in the hippocampus, reduced the expression of Flailer protein and mRNA, when injected at about 3 weeks. This construct rescues some phenotypes, including LTD, anxiety, and contextual fear conditioning memory, but does not rescue the repetitive grooming phenotype. When the same construct is injected at P0 in the cerebral ventricles, it also reduces the expression of Flailer protein and mRNA, and rescues repetitive grooming behavior, in addition to anxiety, contextual fear conditioning memory and seizures.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Flailer mouse was identified as a mouse model that carries a spontaneous non-homologous recombination event that resulted in an extra gene, named Flailer. The Flailer gene (MGI:1858520) is composed of the first two exons of Gnb5 fused in a frame with a mixed intron (Gnb5/Myo5a) and exons 26-40 of Myo5a. Since the Flailer mutation is a partial duplication, every cell also contains the endogenous copies of Gnb5 and Myo5a. The expression of the Flailer fusion protein is controlled by the Gnb5 gene promoter, which is highly and broadly expressed in the central nervous system. The resulting protein, Flailer, binds to cargo but lacks the actin-binding domain of MyosinVa, which is necessary for binding and walking to the plus end of actin filaments. When the Flailer protein is present in a 1:1 ratio with wild-type MyosinVa (homozygous) it works as a dominant negative, leading to a reduced transport and abnormal synaptic clustering of receptors and scaffolding proteins.
Allele Type: Dominant negative
Strain of Origin: C57BL/10J
Genetic Background: B6 x B6CBCa Aw-J
ES Cell Line: NA
Mutant ES Cell Line: Model Source: Jackson Laboratory
Description: Long-term depression by paired-pulse low-frequency stimulation is absent in the hippocampus of the Flailer mouse, while slices from wildtype mice exhibit robust LTD induction.
Description: Flailer mice show increased anxiety behavior in light-dark exploration test, measured by three parameters: increased latency to enter bright field, decreased number of crosses to light and decreased time spent in the bright field.
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Flailer animals do not demonstrate strong memory formation, as measured by reduced freezing times in response to fear-associated context, compared to wildtype animals.
