期刊
HUMAN MOLECULAR GENETICS
卷 27, 期 11, 页码 1892-1904出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy096
关键词
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资金
- Fondazione Bambino Gesu
- Ministero della Salute [RC2016, RC2017]
Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as 'tubulinopathies', characterized by a wide range of neuronal defects resulting from defective proliferation, migration and function. Here, we causally link a previously unreported missense mutation in TUBB2A (c.1249G>A, p.D417N), encoding one of the neuron-specific beta-tubulin isotype II, to a disorder characterized by progressive spastic paraplegia, peripheral sensory-motor polyneuropathy and ataxia. Asp(417) is a highly conserved solvent-exposed residue at the site mediating binding of kinesin superfamily motors. Impaired binding to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors of the disease-associated TUBB2A mutant, was predicted by structural analyses and confirmed experimentally in vitro. We show that overexpression of TUBB2A(D417N) disrupts the mitotic spindle bipolarity and morphology and affects the M phase entry and length. Differently from the TUBB2A(N247K) and TUBB2A(A248V), two mutants previously identified to affect neurodevelopment, TUBB2(AD417N) retains the ability to assemble into microtubules. Consistent with the differential clinical and structural impact, TUBB2A(A248V) does not drastically affect TUBB2A binding to KIF1A, nor mitotic spindle bipolarity. Overall, our data demonstrate a pathogenic role of the p.D417N substitution that is different from previously reported TUBB2A mutations and expand the phenotypic spectrum associated with mutations in this gene.
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