TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Antonella Sferra (1) , Gilbert Baillat (2) , Teresa Rizza (1) , Sabina Barresi (1) , Elisabetta Flex (3) , Giorgio Tasca (1) , Adele D’amico (1) , Emanuele Bellacchio (1) , Andrea Ciolfi (4) , Viviana Caputo (5) , Serena Cecchetti (6) , Annalaura Torella (7) , Ginevra Zanni (1) , Daria Diodato (1) , Emanuela Piermarini (8) , Marcello Niceta (1) , Antonietta Coppola (1) , Enrico Tedeschi (1) , Diego Martinelli (1) , Carlo Dionisi-Vici (7) , Vincenzo Nigro (7) , Bruno Dallapiccola (1) , Claudia Compagnucci (9) , Marco Tartaglia (10) , Georg Haase (2) , Enrico Bertini (1)

1 Medical Genetics and Pediatric Cardiology
2 INT - Institut de Neurosciences de la Timone
3 Department of Hematology, Oncology and Molecular Medicine
4 CREA - Centro di Ricerca per gli alimenti e la nutrizione
5 Department of Experimental Medicine
6 Department of Cell Biology and Neurosciences
7 Department of Biochemistry, Biophysics and General Pathology
8 Division of Metabolism
9 Department of Craniofacial Development & Orthodontics
10 Ematologia, Oncologia e Medicina Molecolare

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.

Domaines: Génétique humaine; Pédiatrie; Neurobiologie

Antonella Sferra, Gilbert Baillat, Teresa Rizza, Sabina Barresi, Elisabetta Flex, et al.. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. American Journal of Human Genetics, 2006, 99 (4), pp.974 - 983. ⟨10.1016/j.ajhg.2016.08.006⟩. ⟨hal-01463875⟩