Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
13
10
2020
accepted:
17
12
2020
revised:
12
12
2020
pubmed:
3
3
2021
medline:
18
1
2022
entrez:
2
3
2021
Statut:
ppublish
Résumé
Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.
Identifiants
pubmed: 33649541
doi: 10.1038/s41431-020-00804-7
pii: 10.1038/s41431-020-00804-7
pmc: PMC8110841
doi:
Substances chimiques
TUBA1A protein, human
0
Tubulin
0
Kinesins
EC 3.6.4.4
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
816-826Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS007473
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY014104
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Organisme : NEI NIH HHS
ID : T32 EY007145
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY027421
Pays : United States
Organisme : NEI NIH HHS
ID : K08 EY027850
Pays : United States
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