Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations

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A spectrum of neurological disorders characterized by abnormal neuronal migration, differentiation, and axon guidance and maintenance have recently been attributed to missense and splice-site mutations in the genes that encode α-tubulin and β-tubulin isotypes TUBA1A, TUBA8, TUBB2B, and TUBB3, all of which putatively coassemble into neuronal microtubules. The resulting nervous system malformations can include different types of cortical malformations, defects in commissural fiber tracts, and degeneration of motor and sensory axons. Many clinical phenotypes and brain malformations are shared among the various mutations regardless of structural location and/or isotype, while others segregate with distinct amino acids or functional domains within tubulin. Collectively, these disorders provide novel paradigms for understanding the biological functions of microtubules and their core components in normal health and disease.

Section snippets

Phenotypic spectrum of the tubulin-related disorders

Twenty-three heterozygous missense mutations in TUBA1A have been reported [1, 2, 3, 4, 5, 6••, 7•]. All are sporadic and likely de novo, and four have been found in more than one unrelated individual. Most children harboring these mutations have microcephaly, severe motor and intellectual disabilities, and seizures. A subset also has simple strabismus and/or facial weakness, but none has paralytic strabismus or congenital fibrosis of the extraocular muscles (CFEOM). Fetopsy and imaging studies

Amino acid substitutions reside in three structural domains of tubulin necessary for microtubule functions

Microtubules are dynamic polymers comprising tandem repeats of αβ tubulin heterodimers, which assemble in a head to tail fashion at the growing ends of microtubules to form a sheet of longitudinal protofilaments. Lateral interactions between neighboring protofilaments cause the sheet to close, thereby forming the hollow, cylindrical microtubule body [12•, 13]. The structural conformation of longitudinal protofilaments is tightly regulated and, therefore, the structures of α-tubulin and

Mutations can alter both the overall abundance and functions of tubulin heterodimers

All mutations reported thus far in TUBA1A, TUBB2B, and TUBB3 have been heterozygous missense mutations. Missense mutations in the absence of nonsense, frameshift, or genomic deletions support altered protein function rather than haploinsufficiency as a primary genetic etiology of these tubulin-related disorders, and this is reinforced by phenotype–genotype correlations associated with recurrent mutations [9••, 31]. By contrast, homozygous splice-site mutations in TUBA8 delete amino acids that

Conclusion

Many questions still remain with regard to how the different mutations in α-tubulin and β-tubulin cause the range of reported neurological impairments and structural brain malformations. At present, much of the evidence supports that the dynamic properties and functions of microtubules are altered in several fashions. These include diminishing the overall abundance of functional tubulin heterodimers, altering GTP binding, altering longitudinal and lateral protofilament interactions, and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was funded by National Institutes of Health NEI R01EY12498. Dr. Engle is an Investigator of the Howard Hughes Medical Institute.

References (37)

  • M. Lecourtois et al.

    Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype

    Acta Neuropathol

    (2010)
  • K. Poirier et al.

    Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A)

    Hum Mutat

    (2007)
  • D.J. Morris-Rosendahl et al.

    Refining the phenotype of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly

    Clin Genet

    (2008)
  • C. Fallet-Bianco et al.

    Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A

    Brain

    (2008)
  • N. Bahi-Buisson et al.

    Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations

    J Med Genet

    (2008)
  • R.A. Kumar et al.

    TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins

    Hum Mol Genet

    (2010)
  • X.H. Jaglin et al.

    Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria

    Nat Genet

    (2009)
  • M.A. Tischfield et al.

    Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance

    Cell

    (2010)
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