Lissencephaly 6 With Microcephaly

A number sign (#) is used with this entry because of evidence that lissencephaly-6 with microcephaly (LIS6) is caused by homozygous mutation in the KATNB1 gene (602703) on chromosome 16q21.

Description

Lissencephaly-6 is an autosomal recessive neurodevelopmental disorder characterized by severe microcephaly and developmental delay. Brain imaging shows variable malformations of cortical development, including lissencephaly, pachygyria, and hypoplasia of the corpus callosum (summary by Mishra-Gorur et al., 2014).

For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).

Clinical Features

Mishra-Gorur et al. (2014) reported clinical details of 7 patients from 5 unrelated families, 4 of whom were consanguineous, with microcephaly and various complex malformations of cortical development. All patients had delayed cognitive development, and most had delayed motor development. Other more variable features included hypertonia, seizures, and nonspecific facial dysmorphism. Brain imaging revealed abnormalities including microlissencephaly, diffuse frontal predominant undersulcation with variable gyral size, mildly thick cortex with subtle irregularity of the cortical-white matter border, pachygyria, polymicrogyria, subcortical or periventricular heterotopia, and hypogenesis of the corpus callosum. The brainstem and cerebellum were relatively preserved. Mishra-Gorur et al. (2014) noted that the phenotype resembled that observed in patients who had LIS4 (614019) caused by mutation in the NDE1 gene (609449).

Hu et al. (2014) reported the clinical features of 5 patients from 3 different consanguineous families with severe microcephaly (up to -5.9 SD) and a simplified gyral pattern on brain imaging. The families were of Jordanian, Saudi Arabian, and Palestinian descent, respectively. All patients had severe global developmental delay without speech. Other neurologic features included spasticity, hyperreflexia, and seizures. Brain imaging showed a dramatically reduced brain size, pachygyria, shallow sulci, enlarged lateral ventricles, and partial agenesis of the corpus callosum. There was relative sparing of the brainstem and cerebellum. Hu et al. (2014) used the term 'microlissencephaly' to describe the disorder, and noted the similarities to those caused by mutations in the NDE1 gene.

Inheritance

The transmission pattern of LIS6 in the families reported by Mishra-Gorur et al. (2014) and Hu et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 probands, born of consanguineous parents, with LIS6, Mishra-Gorur et al. (2014) identified homozygous mutations in the KATNB1 gene (see, e.g., 602703.0001-602703.0003) that segregated with the disorder in the families. The mutations were found by whole-exome sequencing of over 2,000 children with complex malformations of cortical development. A fifth patient with a similar phenotype was subsequently found to carry biallelic KATNB1 mutations. Fibroblasts from selected patients showed reduced levels of KATNB1 without an obvious impact on the microtubule network in interphase cells. However, dividing cells had abnormal mitotic spindles, disorganized microtubules, and aberrant numbers of centrosomes. Knockdown of the Katnb1 gene in zebrafish and Drosophila recapitulated the phenotype of microcephaly and abnormal cell cycle dynamics in neuronal progenitor cells.

In 5 patients from 3 unrelated consanguineous families with LIS6, Hu et al. (2014) identified 3 different homozygous mutations in the KATNB1 gene (602703.0004-602703.0006). The mutations were found by a combination of homozygosity mapping, whole-exome sequencing, and exon sequencing. Patient-derived cells showed decreased levels of KATNB1 and KATNA1 (606696), as well as defects in centrosomal structure and function, mitotic spindle abnormalities, supernumerary chromosomes, and excess kinetochores. These findings were consistent with perturbation of the cell cycle. In vitro cellular knockdown of the KATNB1 gene also caused increased stability of microtubules, extra mother centrioles, and overproduction of cilia, with improper downstream signaling of SHH (600725). Based on animal studies, Hu et al. (2014) concluded that the mutations identified in their patients were hypomorphic, not null.

Animal Model

Mishra-Gorur et al. (2014) found that knockdown of the katnb1 gene in zebrafish resulted in a significant reduction in midbrain size, while Katnb1 knockdown in Drosophila significantly reduced overall brain size. Katnb1 loss in Drosophila resulted in mitotic spindle abnormalities, delayed cell cycle progression, and mitotic failure in asymmetrically dividing neural progenitor cells in the optic lobe. Mutant Drosophila also showed a reduction in dendritic arborization of sensory and motor neurons compared to wildtype.

Hu et al. (2014) found that homozygous loss of the Katnb1 gene in mice was embryonic lethal. Mutant mice had dramatically reduced body size, reduced limb bud outgrowth, microphthalmia to anophthalmia, and forebrain abnormalities ranging from microcephaly to holoprosencephaly. Brains of mutant mice had reduced cycling and proliferating radial neuroepithelial progenitor cells compared to wildtype, with a more profound loss of cells that depended upon asymmetrical cell divisions. These cells also showed evidence of increased apoptosis. Knockdown of the katnb1 gene in zebrafish caused a wide spectrum of defects in gastrulation and formation of anterior structures, ranging from milder microcephaly to more severe anencephaly and early embryonic death. The findings in both animal models indicated that katanin plays a major role during early embryogenesis and patterning of anterior structures.