Refining the phenotype of α‐1a Tubulin (TUBA1A) mutation in patients with classical lissencephaly

Abstract

Mutations in the alpha-1a Tubulin (TUBA1A) gene have recently been found to cause cortical malformations resemblant of classical lissencephaly but with a specific combination of features. To date, TUBA1A mutations have been described in five patients and three foetuses. Our aims were to establish how common TUBA1A mutations are in patients with lissencephaly and to contribute to defining the phenotype associated with TUBA1A mutation. We performed mutation analysis in the TUBA1A gene in 46 patients with classical lissencephaly. In 44 of the patients, mutations in the LIS1 and/or DCX genes had previously been excluded; in 2 patients, mutation analysis was only performed in TUBA1A based on magnetic resonance imaging (MRI) findings. We identified three new mutations and one recurrent mutation in five patients with variable patterns of lissencephaly on brain MRI. Four of the five patients had congenital microcephaly, and all had dysgenesis of the corpus callosum and cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. We estimate the frequency of mutation in TUBA1A gene in patients with classical lissencephaly to be approximately 4%, and although not as common as mutations in the LIS1 or DCX genes, mutation analysis in TUBA1A should be included in the molecular genetic diagnosis of classical lissencephaly, particularly in patients with the combination of features highlighted in this paper.

Brain malformations and mutations in α‐ and β‐tubulin genes: a review of the literature and description of two new cases

“…12,14,16,20 The features of cortical maldevelopment enrich the spectrum of the MCDs tubulin-related disorders described so far: the patient carrying a mutation in the TUBB2B gene (Patient 2) showed areas of nodular heterotopia never before reported; the patients carrying a mutation in the TUBA1A gene presented with pachygyria associated with a diffuse subcortical band heterotopia which, among lissencephaly spectrum disorders, has so far been observed in only two cases, described by MorrisRosendahl et al 27 Additional defects of migration included malformed hippocampi and irregular disposition of the cerebellar folia in the paravermian region in Patient 2.…”

Polarity Regulation in Migrating Neurons in the Cortex

“…Microtubules assembled in vitro from specific tubulin isoforms exhibit different assembly, stability, and dynamic properties [81][82][83]. So far, only mutations in alpha-tubulin 1a have been associated with neuronal migration deficits in humans and in mice [13,[84][85][86][87]. One of the alpha-tubulin mutations associated with human disease has been studied in detail (R264C).…”

Genetics and mechanisms leading to human cortical malformations

“…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].…”

“…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]. Clinical features include motor and intellectual disabilities, epilepsy and ocular impairments.…”