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