Journal article
TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy
American journal of human genetics, v 99(4), pp 974-983
06 Oct 2016
PMID: 27666369
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 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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Details
- Title
- TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy
- Creators
- Antonella Sferra - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyGilbert Baillat - Institut de Neurosciences de la TimoneTeresa Rizza - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalySabina Barresi - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyElisabetta Flex - College Station Medical CenterGiorgio Tasca - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyAdele D'Amico - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyEmanuele Bellacchio - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyAndrea Ciolfi - Istituto Nazionale di Ricerca per gli Alimenti e la NutrizioneViviana Caputo - College Station Medical CenterSerena Cecchetti - Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, ItalyAnnalaura Torella - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyGinevra Zanni - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyDaria Diodato - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyEmanuela Piermarini - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyMarcello Niceta - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyAntonietta Coppola - University of Naples Federico IIEnrico Tedeschi - University of Naples Federico IIDiego Martinelli - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyCarlo Dionisi-Vici - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyVincenzo Nigro - Univ Naples 2, Dept Biochem Biophys & Gen Pathol, I-80138 Naples, ItalyBruno Dallapiccola - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyClaudia Compagnucci - King's College LondonMarco Tartaglia - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, ItalyGeorg Haase - Institut de Neurosciences de la TimoneEnrico Bertini - Osped Pediat Bambino Gesu, Genet & Rare Dis Res Div, I-00146 Rome, Italy
- Publication Details
- American journal of human genetics, v 99(4), pp 974-983
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- RC2015; RC2016 / Ministero della Salute; Ministry of Health, Italy Agence Nationale de la Recherche; Agence Nationale de la Recherche (ANR) Fondazione Bambino Gesu (Vite Coraggiose) Bulgari (GeneRare)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000385333700018
- Scopus ID
- 2-s2.0-84991691574
- Other Identifier
- 991021900206504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity