TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy
Résumé
Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding
tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding
and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey
syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice,
no similar degenerative phenotype has been recognized in humans. We report on the identification of an early-onset and progressive
neurodegenerative encephalopathy with distal spinal muscular atrophy resembling the phenotype of pmn/pmn mice and caused by
biallelic TBCE mutations, with the c.464T>A (p.Ile155Asn) change occurring at the heterozygous/homozygous state in six affected
subjects from four unrelated families originated from the same geographical area in Southern Italy. Western blot analysis of patient
fibroblasts documented a reduced amount of TBCE, suggestive of rapid degradation of the mutant protein, similarly to what was
observed in pmn/pmn fibroblasts. The impact of TBCE mutations on microtubule polymerization was determined using biochemical fractionation
and analyzing the nucleation and growth of microtubules at the centrosome and extracentrosomal sites after treatment with
nocodazole. Primary fibroblasts obtained from affected subjects displayed a reduced level of polymerized a-tubulin, similarly to tail
fibroblasts of pmn/pmn mice. Moreover, markedly delayed microtubule re-polymerization and abnormal mitotic spindles with disorganized
microtubule arrangement were also documented. Although loss of function of TBCE has been documented to impact multiple
developmental processes, the present findings provide evidence that hypomorphic TBCE mutations primarily drive neurodegeneration.
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