Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes

Abstract

Mutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in only 1-13%. We identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. Remarkably, in seven of nine patients (78%), targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Careful re-review of the cortical phenotype on brain imaging revealed only an irregular pattern of gyri and sulci, for which we propose the term tubulinopathy-related dysgyria. Basal ganglia (100%) and brainstem dysplasia (80%) were common features. On the basis of in silico structural predictions, the mutations affect amino acids in diverse regions of the alpha-/beta-tubulin heterodimer, including the nucleotide binding pocket. Cell-based assays of tubulin dynamics reveal various effects of the mutations on incorporation into microtubules: TUBB3 p.Glu288Lys and p.Pro357Leu do not incorporate into microtubules at all, whereas TUBB2B p.Gly13Ala shows reduced incorporation and TUBA1A p.Arg214His incorporates fully, but at a slower rate than wild-type. The broad range of effects on microtubule incorporation is at odds with the highly stereotypical clinical phenotype, supporting differential roles for the three tubulin genes involved. Identifying this highly characteristic phenotype is important due to the low recurrence risk compared with the other (recessive) cerebellar dysplasias and the apparent lack of non-neurological medical issues.

Lissencephaly: Expanded imaging and clinical classification

“…For example, several of the original reports of cortical malformations with tubulin genes ( TUBB2B , TUBB , TUBB3 ) described “polymicrogyria” rather than LIS [Breuss et al, 2012; Jaglin et al, 2009; Poirier et al, 2010]. But our experience and published reports since then have shown that the brain-imaging features are intermediate between LIS (pachygyria) and polymicrogyria, consisting of mixed large and small gyri separated by shallow sulci, a smooth gray-white border and little infolding [Cushion et al, 2013; Mutch et al, 2015; Oegema et al, 2015]. We will refer to this pattern, as suggested by Mutch et al, as tubulinopathy-related dysgyria.…”

GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

“…This has also been referred to as tubulinopathy-related dysgyria. 29 Whereas tubulinopathies are classified as disorders of neuronal migration leading to cortical dysgenesis, 30 PMG is considered to be due to postmigrational disruption of cortical development with fusion of cortical laminae. 31 Knockdown of Grin2b in rat has been shown to disturb proper neuronal migration 32 and glutamate has been implemented in its regulation.…”

The genetics of cerebellar malformations

“…Dysmorphic features are infrequently reported, and, surprisingly, other organ systems are not affected. Most occurrences are sporadic and due to de-novo mutations, but rare recurrences have been reported due to germline mosaicism and autosomal recessive inheritance [14]. …”