Overlapping cortical malformations and mutations in TUBB2B and TUBA1A

Abstract

Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α- and β-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.

Genetics and mechanisms leading to human cortical malformations

“…MCDs present in most individuals with mutations of tubulin or tubulin motor genes include a wide spectrum of morphological abnormalities with overlapping characteristics of LIS and PMG by brain imaging and neuropathological examinations [49,176].…”

“…Mutations in the tubulin α-1A (TUBA1A) gene have been found in patients presenting a wide spectrum of MCDs [49,136,[176][177][178][179]. As well as the cLIS spectrum, brain malformations include lissencephaly with cerebellar hypoplasia, or with corpus callosum agenesis, and centrally predominant pachygyria, PMG-like cortical dysplasia, generalized PMG-like cortical dysplasia, simplified gyral pattern with areas of focal PMG, and microlissencephaly often in combination with dysplastic basal ganglia, corpus callosum abnormalities, and hypoplasia or dysplasia of the brainstem and cerebellum [47,175,177,178].…”

“…Moreover, neuropathological examination of a fetus showed absence of cortical lamination with ectopic neurons in the white matter and in the leptomeningeal spaces as a consequence of breaches in the pial basement membrane [153]. TUBB2B mutations were also identified in symmetric PMG and pachygyria, complex malformations of cortical development, and lissencephaly [176,180]. The analysis of somatic mutations performed by Jamuar and col. [39] in a cohort of 158 patients with MCDs, also found a patient with a pathogenic mutation in TUBB2B presenting frontal pachygyria, parietal, occipital and temporal PMG, a small dysplastic cerebellum, hypoplastic pons and hypoplastic optic nerves.…”

Malformations of Cortical Development and Epilepsy

“…Recent work, however, has shown that all of the six grades of classic lissencephalies (Table 1) are caused by mutations of genes encoding tubulins ( primarily TUBA1A) (Poirier et al 2007) or proteins that function in conjunction with microtubules (microtubule-associated proteins or MAPs, such as DCX, LIS1, cytoplasmic dynein, kinesins, NudE) (Dobyns et al 1993;Gleeson et al 1998;Toyo-oka et al 2003;Lecourtois et al 2010;Cushion et al 2013;Poirier et al 2013). As mutations of genes encoding tubulins and MAPs are associated with, and likely responsible for, other MCDs (such as heterotopia and polymicrogyria [PMG]-like cortex) (Poirier et al , 2012Guerrini et al 2012;Cushion et al 2013), one might consider altering the classification to make malformations secondary to mutations of tubulin and MAP genes as a major category of MCD with classic lissencephalies as a subcategory. It will be interesting to determine what differences are seen in the mutations of genes coding for MAPs as compared with those coding for the tubulins themselves.…”

Participation: remembering the ‘handicap’

“…Recently, mutations in a number of neuron-specific a-and b-tubulin genes (TUBA1A and TUBB2B) have been identified in PMG, usually associated with abnormal cerebral anomalies such as callosal hypoplasia, abnormal basal ganglia, and cerebellar hypoplasia. 2 These findings and other mutations found (such as of GPR56) have led to an increasing search for genetic factors in the pathogenesis of PMG. Mutations of these various genes may lead to radial glial instability via different means, loss of interaction with the basal membrane in the case of GPR56, and cytoskeletal destabilization for TUBB2B.…”