TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy.
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.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Antonella
A
Sferra
Institut de Neurosciences de la Timone, UMR 7289 CNRS Aix-Marseille University, 13005 Marseille, France.
Gilbert
G
Baillat
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Teresa
T
Rizza
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Sabina
S
Barresi
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
Elisabetta
E
Flex
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Giorgio
G
Tasca
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Adele
A
D'Amico
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Emanuele
E
Bellacchio
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy; Centro di Ricerca per gli alimenti e la nutrizione, CREA, 00178 Rome, Italy.
Andrea
A
Ciolfi
Department of Experimental Medicine, Università La Sapienza, 00161 Rome, Italy.
Viviana
V
Caputo
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy.
Serena
S
Cecchetti
Department of Biochemistry, Biophysics and General Pathology, Seconda Università degli Studi di Napoli, 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
Annalaura
A
Torella
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Ginevra
G
Zanni
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Daria
D
Diodato
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Emanuela
E
Piermarini
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Marcello
M
Niceta
Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, 80131 Naples, Italy.
Antonietta
A
Coppola
Department of Advanced Biomedical Sciences, Università degli Studi di Napoli Federico II, 80131 Naples, Italy.
Enrico
E
Tedeschi
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Diego
D
Martinelli
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Carlo
C
Dionisi-Vici
Department of Biochemistry, Biophysics and General Pathology, Seconda Università degli Studi di Napoli, 80138 Naples, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
Vincenzo
V
Nigro
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Bruno
B
Dallapiccola
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Claudia
C
Compagnucci
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
Marco
M
Tartaglia
Institut de Neurosciences de la Timone, UMR 7289 CNRS Aix-Marseille University, 13005 Marseille, France.
Georg
G
Haase
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy. Electronic address: bertini@opbg.net.
Enrico
E
Bertini
D000293:Adolescent; D017668:Age of Onset; D000818:Animals; D001927:Brain Diseases / Q000150:complications* / Q000235:genetics*; D002648:Child; D005260:Female; D005347:Fibroblasts; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D015739:Nocodazole / Q000494:pharmacology; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D055815:Young Adult
D018832:Molecular Chaperones; C469270:TBCE protein, human; D014404:Tubulin; D015739:Nocodazole
Hum Mutat. 2013 Sep;34(9):E2393-402
23843252
Front Neurosci. 2015 Nov 10;9:431
26617483
Nat Genet. 2002 Nov;32(3):448-52
12389028
Neuron. 2015 Aug 5;87(3):492-506
26247859
Am J Hum Genet. 2013 May 2;92(5):767-73
23582646
J Biol Chem. 1991 Feb 25;266(6):3987-94
1671676
Cell Mol Life Sci. 2008 Aug;65(15):2307-33
18408889
Hum Mol Genet. 2015 Apr 15;24(8):2125-37
25552646
J Cell Biol. 2002 Nov 25;159(4):563-9
12446740
Brain. 2014 Jun;137(Pt 6):1676-700
24860126
J Neurosci. 2007 Aug 15;27(33):8779-89
17699660
Nat Genet. 2014 Aug;46(8):815-7
25017102
Neuron. 2014 Oct 22;84(2):324-31
25374358
J Neuropathol Exp Neurol. 1991 May;50(3):192-204
2022963
Genome Res. 2010 Sep;20(9):1297-303
20644199
Cell Mol Life Sci. 2010 Jun;67(12 ):2025-38
20204449
Am J Med Genet A. 2006 Mar 15;140(6):611-7
16470743
Am J Pathol. 1992 Mar;140(3):731-7
1546747
Am J Hum Genet. 2015 May 7;96(5):816-25
25865493
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13491-6
16938882
Hum Mol Genet. 2014 Nov 15;23(22):5961-75
24951541
Nat Genet. 2002 Nov;32(3):443-7
12389029
Fly (Austin). 2012 Apr-Jun;6(2):80-92
22728672
Nat Genet. 2014 Mar;46(3):310-5
24487276
Electrophoresis. 1997 Dec;18(15):2714-23
9504803
J Cell Sci. 2015 May 1;128(9):1824-34
25908846
Nat Genet. 2015 Jun;47(6):661-7
25915598
Neuropathol Appl Neurobiol. 2016 Apr;42(3):220-41
25870938
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5472-7
8643599
J Mol Biol. 1993 Dec 5;234(3):779-815
8254673