In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described.
Over the years other phenotypes including Charcot Marie Tooth type 2 and hereditary mental retardation with cortical neural migration defects have also been reported to be caused by DYNC1H1 mutations.
FLNAp.V528M was initially detected in a female autopsy case of X-linked bilateral periventricular nodular heterotopia (BPNH), a neuronal migration disorder characterized by subependymal nodules of gray matter.
Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering.
Subcortical band heterotopia (SBH) is a neuronal migration disorder usually described in females carrying heterozygous mutations in the X-linked doublecortin (DCX) gene.
Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects.
De novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders, ranging from lissencephaly to perisylvian pachygyria.
Underlying causes were identified in 15 children (65%) and included SCN1A-related Dravet syndrome (formerly severe myoclonic epilepsy of infancy) or genetic epilepsy with febrile seizures plus syndrome (n = 8 and n = 1, respectively), a protocadherin 19 mutation, a 1qter microdeletion, neuronal migration disorders (n = 2), and other monogenic familial epilepsy (n = 2).
Mouse models confirm that 14-3-3epsilon plays an important role in neuronal migration, and mice that are double heterozygotes for mutations in Lis1 and 14-3-3epsilon, display more severe neuronal migration defects.
Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome.
Sequence analysis revealed a striking identity (99%) of the subunit with a protein encoded by the causative gene (LIS-1) for Miller-Dieker lissencephaly, a human brain malformation manifested by a smooth cerebral surface and abnormal neuronal migration.
Since microtubule (MT) and actin-associated proteins play important functions in regulating the dynamics of MT and actin cytoskeletons during neuronal migration, genetic mutations or deletions of crucial genes involved in cytoskeletal processes lead to lissencephaly in human and neuronal migration defects in mouse.