Limits...
Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Fallet-Bianco C, Laquerrière A, Poirier K, Razavi F, Guimiot F, Dias P, Loeuillet L, Lascelles K, Beldjord C, Carion N, Toussaint A, Revencu N, Addor MC, Lhermitte B, Gonzales M, Martinovich J, Bessieres B, Marcy-Bonnière M, Jossic F, Marcorelles P, Loget P, Chelly J, Bahi-Buisson N - Acta Neuropathol Commun (2014)

Bottom Line: The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13).The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7).Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

View Article: PubMed Central - PubMed

Affiliation: Institut Imagine, Université Paris Descartes - Sorbonne Paris Cités, Paris, France. nadia.bahi-buisson@nck.aphp.fr.

ABSTRACT
Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

Show MeSH

Related in: MedlinePlus

Schematic representation of the functional domains of TUBA1A, TUBB2B and TUBB3 tubulin subunits and distribution of mutations associated with foetal cases with malformations of cortical development. Illustrated domains are the N-terminal that contains the guanine nucleotide-binding region, intermediate domain, and C-terminal domains that constitutes the binding surface for MAPs and molecular motors such as kinesins and dyneins. In β-tubulin, they correspond to residues 1–229, 230–371, and 372–450, [36] and in α-tubulin, to residues 1–205, 206–381, 382–451 [37], respectively. Mutations associated with a lissencephaly (classical and with cerebellar hypoplasia) phenotype are indicated in red, with microlissencephaly in green, with polymicrogyria-like cortical dysplasia in pink. For recurrent variations the number of occurrences is indicated in brackets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4222268&req=5

Fig1: Schematic representation of the functional domains of TUBA1A, TUBB2B and TUBB3 tubulin subunits and distribution of mutations associated with foetal cases with malformations of cortical development. Illustrated domains are the N-terminal that contains the guanine nucleotide-binding region, intermediate domain, and C-terminal domains that constitutes the binding surface for MAPs and molecular motors such as kinesins and dyneins. In β-tubulin, they correspond to residues 1–229, 230–371, and 372–450, [36] and in α-tubulin, to residues 1–205, 206–381, 382–451 [37], respectively. Mutations associated with a lissencephaly (classical and with cerebellar hypoplasia) phenotype are indicated in red, with microlissencephaly in green, with polymicrogyria-like cortical dysplasia in pink. For recurrent variations the number of occurrences is indicated in brackets.

Mentions: Genetic and molecular investigations of foetal cases with complex malformations of cortical development allowed us to identify TUBA1A, TUBB2B and TUBB3 mutations in 26 out of the 60 cases (43.3%) referred to our laboratories (Cochin Hospital and Cochin Institute Laboratories). Of these, we found 19 TUBA1A, 6 TUBB2B and 1 TUBB3 mutations. All mutations were different missense mutations, and were shown to occur de novo. Of these 26, 19 are newly reported. The 7 foetuses that had been previously reported were reanalysed for the purpose of the study (see for detailed results Figure 1 and Tables 1, 2 and 3).Figure 1


Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Fallet-Bianco C, Laquerrière A, Poirier K, Razavi F, Guimiot F, Dias P, Loeuillet L, Lascelles K, Beldjord C, Carion N, Toussaint A, Revencu N, Addor MC, Lhermitte B, Gonzales M, Martinovich J, Bessieres B, Marcy-Bonnière M, Jossic F, Marcorelles P, Loget P, Chelly J, Bahi-Buisson N - Acta Neuropathol Commun (2014)

Schematic representation of the functional domains of TUBA1A, TUBB2B and TUBB3 tubulin subunits and distribution of mutations associated with foetal cases with malformations of cortical development. Illustrated domains are the N-terminal that contains the guanine nucleotide-binding region, intermediate domain, and C-terminal domains that constitutes the binding surface for MAPs and molecular motors such as kinesins and dyneins. In β-tubulin, they correspond to residues 1–229, 230–371, and 372–450, [36] and in α-tubulin, to residues 1–205, 206–381, 382–451 [37], respectively. Mutations associated with a lissencephaly (classical and with cerebellar hypoplasia) phenotype are indicated in red, with microlissencephaly in green, with polymicrogyria-like cortical dysplasia in pink. For recurrent variations the number of occurrences is indicated in brackets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222268&req=5

Fig1: Schematic representation of the functional domains of TUBA1A, TUBB2B and TUBB3 tubulin subunits and distribution of mutations associated with foetal cases with malformations of cortical development. Illustrated domains are the N-terminal that contains the guanine nucleotide-binding region, intermediate domain, and C-terminal domains that constitutes the binding surface for MAPs and molecular motors such as kinesins and dyneins. In β-tubulin, they correspond to residues 1–229, 230–371, and 372–450, [36] and in α-tubulin, to residues 1–205, 206–381, 382–451 [37], respectively. Mutations associated with a lissencephaly (classical and with cerebellar hypoplasia) phenotype are indicated in red, with microlissencephaly in green, with polymicrogyria-like cortical dysplasia in pink. For recurrent variations the number of occurrences is indicated in brackets.
Mentions: Genetic and molecular investigations of foetal cases with complex malformations of cortical development allowed us to identify TUBA1A, TUBB2B and TUBB3 mutations in 26 out of the 60 cases (43.3%) referred to our laboratories (Cochin Hospital and Cochin Institute Laboratories). Of these, we found 19 TUBA1A, 6 TUBB2B and 1 TUBB3 mutations. All mutations were different missense mutations, and were shown to occur de novo. Of these 26, 19 are newly reported. The 7 foetuses that had been previously reported were reanalysed for the purpose of the study (see for detailed results Figure 1 and Tables 1, 2 and 3).Figure 1

Bottom Line: The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13).The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7).Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

View Article: PubMed Central - PubMed

Affiliation: Institut Imagine, Université Paris Descartes - Sorbonne Paris Cités, Paris, France. nadia.bahi-buisson@nck.aphp.fr.

ABSTRACT
Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

Show MeSH
Related in: MedlinePlus