Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway.
Mutation in a growing spectrum of genes is known to either cause or contribute to primary or secondary microcephaly. In primary microcephaly the genetic determinants frequently involve mutations that contribute to or modulate the microtubule cytoskeleton by causing perturbations of neuronal proliferation and migration. Here we describe four patients from two unrelated families each with an infantile neurodegenerative disorder characterized by loss of developmental milestones at 9–24 months of age followed by seizures, dystonia and acquired microcephaly. The patients harboured homozygous missense mutations (A475T and A586V) in TBCD, a gene encoding one of five tubulin-specific chaperones (termed TBCA-E) that function in concert as a nanomachine required for the de novo assembly of the α/β tubulin heterodimer. The latter is the subunit from which microtubule polymers are assembled. We found a reduced intracellular abundance of TBCD in patient fibroblasts to about 10% (in the case of A475T) or 40% (in the case of A586V) compared to age-matched wild type controls. Functional analyses of the mutant proteins revealed a partially compromised ability to participate in the heterodimer assembly pathway. We show via in utero shRNA-mediated suppression that a balanced supply of tbcd is critical for cortical cell proliferation and radial migration in the developing mouse brain. We conclude that TBCD is a novel functional contributor to the mammalian cerebral cortex development, and that the pathological mechanism resulting from the mutations we describe is likely to involve compromised interactions with one or more TBCD-interacting effectors that influence the dynamics and behaviour of the neuronal cytoskeleton.
Neuropediatric Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.|Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
Shimon
S
Edvardson
Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY, USA.
Guoling
G
Tian
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.
Hayley
H
Cullen
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.
Hannah
H
Vanyai
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.
Linh
L
Ngo
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.
Saiuj
S
Bhat
Neuropediatric Unit, Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
Adi
A
Aran
Neuropediatric Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Muhannad
M
Daana
Department of Pediatrics and Genetics, Makassed Hospital, Al-Quds Medical School, Jerusalem.
Naderah
N
Da'amseh
Department of Pediatrics and Genetics, Makassed Hospital, Al-Quds Medical School, Jerusalem.
Bassam
B
Abu-Libdeh
Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY, USA.
Nicholas J
NJ
Cowan
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia, Australia.
Julian Ik-Tsen
JI
Heng
Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center Jerusalem, Jerusalem, Israel.
Orly
O
Elpeleg
D000818:Animals; D001921:Brain / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL / Q000196:embryology; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000502:physiology; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D000073359:Exome Sequencing / Q000379:methods
D008869:Microtubule-Associated Proteins; C418662:TBCD protein, human; D014404:Tubulin