title: A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.
abstract: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and β-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.forename: Nathan
authors.initials: N
authors.lastname: McNeil
authors.forename: Ljubica
authors.initials: L
authors.lastname: Caldovic
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Devaney
authors.forename: Asako
authors.initials: A
authors.lastname: Takanohashi
authors.forename: Joanna
authors.initials: J
authors.lastname: Crawford
authors.forename: Kelin
authors.initials: K
authors.lastname: Ru
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.forename: Davide
authors.initials: D
authors.lastname: Tonduti
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Schmidt
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chudnow
authors.forename: Rudy
authors.initials: R
authors.lastname: van Coster
authors.forename: Lieven
authors.initials: L
authors.lastname: Lagae
authors.forename: Jill
authors.initials: J
authors.lastname: Kisler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sperner
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Taft
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
mesh_terms: D000595:Amino Acid Sequence; D001479:Basal Ganglia / Q000473:pathology*; D001483:Base Sequence; D002531:Cerebellum / Q000473:pathology*; D018360:Crystallography, X-Ray; D059472:Exome / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D014404:Tubulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C582076:TUBB4A protein, human; D014404:Tubulin