Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development

Abstract

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.

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

“…The only implicated pathogenic TUBB2B amino acid substitution, E421K, was revealed to lead to primary axonal dysinnervation and a consequent CFEOM-3 phenotype in a dominant manner. All three TUBA1A mutations (H406D, R156H, and M398R) predicted to be detrimental in three unrelated probands were reported in the same research by Jurgens et al in 2021, causing either CFEOM-1 or CFEOM-3 [ 58 ]. Protein structural modeling suggests that these variants affected either the assembly of microtubules or interactions with the motor domain of kinesin-1.…”

“…This is probably due to the fact that mutations in TUBB2B or TUBA1A were generally more deleterious than those in TUBB3 , bringing about a higher incidence of embryonic lethality [ 57 ]. To date, only one and three heterozygous missense mutations in TUBB2B and TUBA1A , respectively, have been identified in CFEOM pedigrees, with or without MCD [ 57 , 58 ]. As expected, some of the affected individuals also had neurological malformations.…”

MAPping tubulin mutations

“…Known collectively as the ‘tubulinopathies’, this disease spectrum encompasses numerous neurodevelopmental disorders including, microcephaly, lissencephaly, and polymicrogyria, reflecting the large number of tubulin genes expressed during embryonic brain formation (e.g., TUBA1A , TUBB2A , TUBB2B , TUBB3 , TUBB5 ) ( Keays et al, 2007 ; Jaglin et al, 2009 ; Poirier et al, 2010 ; Breuss et al, 2012 ; Cushion et al, 2014 ; Romaniello et al, 2018 ). In addition to cortical malformations, the tubulinopathies also include disorders of ocular motor function (associated with variants in TUBB3 , TUBB2B & TUBA1A ), whispering dysphonia ( TUBB4A ), amyotrophic lateral sclerosis ( TUBA4A ), female meiotic infertility ( TUBB8 ), Leber congenital amaurosis with hearing loss ( TUBB4B ), and macrothrombocytopaenia ( TUBB1 ) ( Kunishima et al, 2009 ; Bahi-Buisson et al, 2014 ; Smith et al, 2014 ; Feng et al, 2016 ; Luscan et al, 2017 ; Strassel et al, 2019 ; Jurgens et al, 2021 ; Kimmerlin et al, 2022 ). Irrespective of the clinical attributes of the disease the tubulinopathies are predominantly due to de novo heterozygous, missense mutations and are predicted to act in a gain-of-function manner in most instances ( Figure 1 ) ( Romaniello et al, 2018 ; Leca et al, 2020 ).…”

Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder

“…CCDDs are congenital disorders resulting in absent or aberrant innervation of extraocular and/or cranial musculature. These are typically caused by variants that affect either motor neuron specification or motor nerve development, and include involvement of the kinesin motor protein KIF21A; the tubulin isotypes TUBB3, TUBB2B, or TUBA1A; or transcription factors that, when mutated, cause syndromic conditions with associated cranial nerves axonal guidance dysfunction (Jurgens et al, 2021; Whitman & Engle, 2017).…”