DPYSL5encodes a member of the Dihydropyrimidinase-like (DPYSL) proteins, also designated as the Collapsin response mediators (CRMP) proteins, which constitute a family of five cytosolic phosphoproteins abundantly expressed in the developing nervous system. The DPYSL proteins mediate signals for numerous intracellular/extracellular pathways and play major roles in variety of cellular process including cell migration, neurite extension, axonal guidance, dendritic spine development and synaptic plasticity. The DPYSL proteins associate generally in homo-tetramer or hetero-tetramer complexes with single or multiple isoforms.
Each DPYSL protein displays a distinct subcellular neuronal localization both in time and space demonstrating their divergent functions during development. DPYSL5 forms a ternary complex with tubulin and microtubule associated protein 2 (MAP2) and inhibits the neurites outgrowth by reducing DPYSL2-tubulin interaction complex. It is thus a crucial regulator of neurite and dendrite growth dynamics during neuronal development.
In the initial genetic study, two heterozygous missense variants were identified in nine families including patients with ID associated with cerebral malformations: a recurrent de novo variant p.Glu41Lys has been identified in eight unrelated subjects with ID, corpus callosum agenesis and posterior fossa abnormalities. Furthermore, a p.Gly47Arg variant was found in the family describing the Ritscher-Schinzel syndrome. All individuals with p.Glu41Lys and p.Gly47Arg mutations in DPYSL5display an agenesis of corpus callosum which is a neuroanatomical malformation already associated with ASD and ID.
Functional analyses in primary neuronal cultures overexpressing missense variants of DPYSL5 results in the loss of the inhibitory regulation of DPYSL5 on dendritic growth. Both mutations altered the function of DPYSL5 by preventing the formation of the complex with MAP2 and βIII-Tubulin. In addition, p.Gly47Arg substitution increased the binding of DPYSL5 to DPYSL2.
DPYSL5