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

Antonella Sferra, Gilbert Baillat, Teresa Rizza, Sabina Barresi, Elisabetta Flex, Giorgio Tasca, Adele D'Amico, Emanuele Bellacchio, Andrea Ciolfi, Viviana Caputo, Serena Cecchetti, Annalaura Torella, Ginevra Zanni, Daria Diodato, Emanuela Piermarini, Marcello Niceta, Antonietta Coppola, Enrico Tedeschi, Diego Martinelli, Carlo Dionisi-Vici & 6 others Vincenzo Nigro, Bruno Dallapiccola, Claudia Compagnucci, Marco Tartaglia, Georg Haase, Enrico Bertini

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 α-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.

Original languageEnglish
Pages (from-to)974-983
Number of pages10
JournalAmerican Journal of Human Genetics
Volume99
Issue number4
DOIs
Publication statusPublished - Oct 6 2016

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Spinal Muscular Atrophy
Brain Diseases
Tubulin
Microtubules
Fibroblasts
Mutation
Polymerization
Nocodazole
Phenotype
Centrosome
Spindle Apparatus
Missense Mutation
Mutant Proteins
Neurodegenerative Diseases
Italy
Tail
Protein Isoforms
Western Blotting
Growth
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. / Sferra, Antonella; Baillat, Gilbert; Rizza, Teresa; Barresi, Sabina; Flex, Elisabetta; Tasca, Giorgio; D'Amico, Adele; Bellacchio, Emanuele; Ciolfi, Andrea; Caputo, Viviana; Cecchetti, Serena; Torella, Annalaura; Zanni, Ginevra; Diodato, Daria; Piermarini, Emanuela; Niceta, Marcello; Coppola, Antonietta; Tedeschi, Enrico; Martinelli, Diego; Dionisi-Vici, Carlo; Nigro, Vincenzo; Dallapiccola, Bruno; Compagnucci, Claudia; Tartaglia, Marco; Haase, Georg; Bertini, Enrico.

In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 974-983.

Research output: Contribution to journalArticle

Sferra, Antonella ; Baillat, Gilbert ; Rizza, Teresa ; Barresi, Sabina ; Flex, Elisabetta ; Tasca, Giorgio ; D'Amico, Adele ; Bellacchio, Emanuele ; Ciolfi, Andrea ; Caputo, Viviana ; Cecchetti, Serena ; Torella, Annalaura ; Zanni, Ginevra ; Diodato, Daria ; Piermarini, Emanuela ; Niceta, Marcello ; Coppola, Antonietta ; Tedeschi, Enrico ; Martinelli, Diego ; Dionisi-Vici, Carlo ; Nigro, Vincenzo ; Dallapiccola, Bruno ; Compagnucci, Claudia ; Tartaglia, Marco ; Haase, Georg ; Bertini, Enrico. / TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 4. pp. 974-983.
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AU - Sferra, Antonella

AU - Baillat, Gilbert

AU - Rizza, Teresa

AU - Barresi, Sabina

AU - Flex, Elisabetta

AU - Tasca, Giorgio

AU - D'Amico, Adele

AU - Bellacchio, Emanuele

AU - Ciolfi, Andrea

AU - Caputo, Viviana

AU - Cecchetti, Serena

AU - Torella, Annalaura

AU - Zanni, Ginevra

AU - Diodato, Daria

AU - Piermarini, Emanuela

AU - Niceta, Marcello

AU - Coppola, Antonietta

AU - Tedeschi, Enrico

AU - Martinelli, Diego

AU - Dionisi-Vici, Carlo

AU - Nigro, Vincenzo

AU - Dallapiccola, Bruno

AU - Compagnucci, Claudia

AU - Tartaglia, Marco

AU - Haase, Georg

AU - Bertini, Enrico

PY - 2016/10/6

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N2 - 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 α-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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