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.

Using whole-exome sequencing to identify variants inherited from mosaic parents

“…The causal variant was previously reported after identifying a single de novo missense variant c.745G4A, p.(Asp249Asn) (NM_006087.2) in the TUBB4A gene in six families, as well as three additional patients for whom parental genotypes were unavailable. 13 The quartet reported here is suspected to be the same as in the previous report; where the TUBB4A variant was inherited in both affected siblings from their mother who was mosaic for the variant. We sought to determine the likelihood of our approach to identify the TUBB4A variant using only WES of this quartet.…”

“…Using WES of 13 parent-child trios, we show the potential of WES to identify a modest number of candidate genes under this inheritance model, which has been shown previously to be associated with HABC, 13 Kleefstra syndrome 18 and X-linked severe combined immunodeficiency 19 and may be relevant for seemingly recessive or sporadic disorders for which WES has failed to identify diseasecausing genes. Although it is possible that variants may be inherited from mosaic fathers, in all studies mentioned above, disease-causing variants were inherited from mosaic mothers; which further reduces the number of candidate genes when applied to our families (Table 1).…”

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations

“…As a few patients show signs of osteosclerosis, 11 we hypothesize that a defect of osteoclasts is at the basis of the dentition abnormalities by preventing normal tooth eruption, which necessitates local bone resorption. Regarding the white matter abnormalities, it emerges that defects of proteins essential for RNA synthesis-RNA polymerase III in 4H leukodystrophy, cytoplasmic aspartyl tRNA synthetase in hypomyelination with brainstem involvement and leg spasticity 16 -cause hypomyelination, but the underlying mechanism is unresolved. Which cell type is primarily affected in 4H leukodystrophy, the oligodendrocytes providing the myelin sheath or the neurons whose axonal integrity is essential to induce myelination, remains unclear.…”

TUBB4A de novo mutations cause isolated hypomyelination

“…2,3 In DYT4, an autosomal dominant mutation (c.4C.G [p.Arg2Gly]) in TUBB4A (NM_006087.2) was identified in patients presenting with a "whispering" dysphonia, generalized dystonia, and gait ataxia, but normal MRI features. 2 In H-ABC, a cohort of 11 individuals were found to have a common de novo mutation at c.745G.A (p.Asp249Asn) in TUBB4A.…”

“…2 In H-ABC, a cohort of 11 individuals were found to have a common de novo mutation at c.745G.A (p.Asp249Asn) in TUBB4A. 3 H-ABC is a rare leukodystrophy diagnosed on the basis of distinctive MRI findings including hypomyelination, cerebellar atrophy, and absence or disappearance of the putamen at an early age. 4,5 Individuals with H-ABC present with developmental delay, extrapyramidal movement disorders (dystonia, choreoathetosis, rigidity, opisthotonos, and oculogyric crises), ataxia, and spastic tetraplegia with variable onset and in some cases seizures.…”