Clinical ObservationsTUBA1A Mutation Associated With Eye Abnormalities in Addition to Brain Malformation
Introduction
TUBA1A (OMIM #605529) is a gene encoding tubulin alpha-1A, a protein with an important role in microtubule function and stability.1 Human mutations can result in a wide spectrum of malformations, most of which are thought secondary to defective neuronal migration and/or proliferation, including lissencephaly, microlissencephaly, cerebellar hypoplasia, agenesis of the corpus callosum, pachygyria, and polymicrogyria.2, 3 Although TUBA1A is expressed in both the fetal brain4 and the retina,5 reported cases of TUBA1A mutations have thus far been limited to descriptions of brain malformations without major ophthalmologic abnormalities. We present a patient with TUBA1A mutation and associated developmental ophthalmologic abnormalities, in addition to microcephaly and a typical pattern of brain malformation, further expanding the phenotypic spectrum for mutations in this gene.
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Patient Description
This 19-month-old boy was born at term following a generally uncomplicated pregnancy. An ultrasound at 20 weeks' gestation queried abnormal brain structure; however, a follow-up study was reported as normal and the parents declined further imaging or other testing. He had significant microcephaly from birth (greater than 2 standard deviations below the third percentile) with weight and length following the 25th-50th percentiles. There was no known family history of congenital anomalies and no
Discussion
We present a boy with a previously unreported TUBA1A mutation presenting with ophthalmological abnormalities in addition to a pattern of brain malformation frequently seen with mutations in this gene. The TUBA1A mutation is thought to be pathogenic because the mutation is novel and de novo, and this genomic region is highly conserved. The known expression of TUBA1A in the retina as well as the developing brain lends further credence to this hypothesis. Additionally, a mutation previously
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Cited by (21)
Development of the human olfactory system
2019, Handbook of Clinical NeurologyCitation Excerpt :Arrhinencephaly in Kallmann syndrome also is associated with anomalies of the ethmoid bone that can be demonstrated by computed tomography (Maione et al., 2013). Other genetic syndromes in which brain with dysplasia of the olfactory bulb or epithelium may occur include TUBA1A mutations (Myers et al., 2015), Prader–Willi syndrome (Khor et al., 2016), Bardet–Biedl syndrome (Suspitsin and Imyanitov, 2016), and various congenital heart malformations (Panigrahy et al., 2016). In Waardenburg syndrome due to SOX10 mutations, 7 of 8 patients were anosmic, and arrhinencephaly was demonstrated by imaging (Elmach-Bergès et al., 2013).
Tubulin genes and malformations of cortical development
2018, European Journal of Medical GeneticsCitation Excerpt :One isolated instance of Hirschsprung disease and Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), in addition to agyria with microcephaly, has been described in a girl harbouring a novel TUBA1A variant predicted to cause a p. Cys200Tyr substitution (reported as p. Cys402Tyr) (Hikita et al., 2013). Two individuals with hydranencephaly-like cortical dysgeneses were identified as having p. Cys25Phe and p. Arg64Trp substitutions (Yokoi et al., 2015), and a p. Ala270Ser variant in a boy presenting with microphthalmia and congenital cataracts in addition to microcephaly and mildly simplified cerebral gyral patterning (Myers et al., 2015). At present, the vast majority of TUBA1A mutations described are de novo, heterozygous missense variations.
Insights on the Role of α- and β-Tubulin Isotypes in Early Brain Development
2023, Molecular NeurobiologyDeciphering the Tubulin Language: Molecular Determinants and Readout Mechanisms of the Tubulin Code in Neurons
2023, International Journal of Molecular SciencesNovel loss of function mutation in TUBA1A gene compromises tubulin stability and proteostasis causing spastic paraplegia and ataxia
2023, Frontiers in Cellular Neuroscience
Funding Source: No external funding was secured for this study.
Financial Disclosure Statement: The authors have no financial relationships relevant to this article to disclose.
Conflict of Interest Statement: The authors have no conflicts of interest to disclose.