Aug 2026· Orphanet Journal of Rare Diseases· 0 citations
TL;DR
It is indicated that reduced protein stability and functional impairment of β-tubulin represent key pathogenic mechanisms underlying this condition, and the experimental evidence further supports the implication of TUBB dysfunctions in haematological abnormalities.
Abstract
Tubulinopathies constitute a growing and heterogeneous class of disorders caused by pathogenic variants in genes encoding for tubulins, the structural components of microtubules. These conditions encompass a broad spectrum of neurological manifestations, most commonly including structural brain malformations and, less frequently, neurodegenerative disorders. In addition to brain diseases, tubulinopathies also include non-neurological conditions, such as female meiotic infertility and bleeding disorders. Among tubulin genes,
TUBB
, encoding the class I β-tubulin, has been associated with a wide range of clinical conditions, primarily including neurodevelopmental delay, structural brain abnormalities, and skin creases. More recently,
TUBB
has also been linked to inherited macrothrombocytopaenia, suggesting a broader, yet still incompletely defined, role of this β-tubulin in haematopoiesis and platelet biogenesis. In this study, we aim to investigate pathogenic mechanisms of a novel frameshift variant in
TUBB
(c.628dup; p.Ile210AsnfsTer40), identified in a subject affected by thrombocytopaenia and neurological involvement.
Functional analyses demonstrated that the p.Ile210AsnfsTer40
TUBB
mutation leads to the production of a truncated β-tubulin with reduced protein stability and aberrant subcellular localization. The mutant protein showed impaired interaction with α-tubulin and kinesin family member 1 A (KIF1A), suggesting defective microtubule assembly and microtubule-mediated intracellular transport. Furthermore, the inhibition of the proteasome degradative pathway resulted in a marked increase of the mutant TUBB, indicating altered proteostasis and enhanced degradation of the truncated tubulin. Finally, we showed that the p.Asp249Val substitution in
TUBB
, previously associated with macrothrombocytopaenia, similarly reduces protein stability, weakens interaction with α-tubulin, and impairs TUBB incorporation into microtubules.
This study associates the novel heterozygous truncating p.Ile210AsnfsTer40 variant in
TUBB
with a multisystem disorder characterized by haematological and neurological manifestations, expanding the phenotypic spectrum of
TUBB
-related diseases. Our findings indicate that reduced protein stability and functional impairment of β-tubulin represent key pathogenic mechanisms underlying this condition. Lastly, our experimental evidence further supports the implication of
TUBB
dysfunctions in haematological abnormalities, offering additional insight into the molecular basis and clinical variability of tubulin-related disorders.
Most pathogenic tubulin variants arise de novo in sporadic patients, causing severe brain malformations and significant neurodevelopmental impairment. The resulting reproductive disadvantage typically prevents these mutations from being transmitted to offspring. While a few variants are inherited from somatic or gonadal mosaic parents, vertical transmission of constitutional variants remains rare, though increasingly documented. Here, we report the father-to-daughter transmission of a novel constitutional TUBB variant [NM_178014.4:c.991C>T; p.(Leu331Phe)]. Both individuals presented with intellectual disability and a malformation of cortical development (MCD). To validate the pathogenicity of this variant, we performed functional and immunofluorescence assays in vitro on patient-derived fibroblast cultures. These experiments supported the involvement of the variant in significantly impairing cell motility, altering cytoskeleton organization, and affecting cellular morphology. Our findings from this family, alongside literature review of constitutional and mosaic tubulinopathies, suggest that pathogenic germline TUBB variants can occasionally be inherited. Transmission is facilitated by the relatively mild clinical anatomoclinical phenotype. When a pathogenic TUBB variant is identified in an index patient, comprehensive parental clinical, neuroradiological, and genetic evaluation is crucial to accurately assess reproductive risk.
E. Cellini, D. Mei, Mara Cavallin et al.· American Journal of Medical...· 0 citations
A multicenter retrospective analysis of 15 pediatric patients from 12 unrelated families with genetically confirmed tubulinopathies across five tertiary centers in Turkey identified a rare case of TUBGCP2-related tubulinopathy presenting with cystic leukomalacia, expanding the known radiological spectrum.
Mert Altıntaş, M. Yıldırım, Serkan Kırık et al.· Neurological Sciences· 0 citations
There is moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype, suggesting that the allelic and clinical heterogeneity of HARS1‐related disease is expanded.
Christina Del Greco, Allison R. Cale, Karl Haeberlein et al.· Journal of the peripheral ne...· 0 citations
BACKGROUND
Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals.
METHODS
Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level.
RESULTS
A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases.
CONCLUSION
A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
A. Murtazina, Eugenii Tatarsky, I. Viakhireva et al.· Journal of Medical Genetics· 0 citations
CLDN11 has recently been associated with hypomyelinating leukodystrophy caused by de novo stop-loss variants. Here, we present a new case involving a homozygous variant in order to expand the genetic and clinical spectrum of the disease. We performed a comprehensive clinical, neuroradiological, and genetic evaluation in a child presenting with global developmental delay. Brain MRI and MR spectroscopy were obtained, and next-generation sequencing with parental segregation analysis was conducted. The patient presented with developmental delay, hypotonia, limb hypertonia, esotropia, and an absence of early developmental milestones in infancy, followed by partial motor improvement and persistent language and cognitive impairment. Brain MRI revealed diffuse supratentorial hypomyelination with stability over time. Genetic analysis identified a novel homozygous CLDN11 start-loss variant (c.1A>G; p.Met1Val), which is predicted to result in biallelic loss of function. Both parents were found to be heterozygous carriers. This case supports an autosomal recessive mechanism of CLDN11-related disease, which differs from the dominant stop-loss variants reported previously. The phenotype partially overlaps with that of earlier cases, but is characterized by milder motor involvement and more pronounced cognitive impairment. These findings broaden the mutational spectrum and suggest distinct pathogenic mechanisms, with important implications for diagnosis and genetic counselling.
F. Acquaviva, S. Troisi, G. Errichiello et al.· Clinical Genetics· 0 citations
A case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports and helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.
D. Latner, S. Hiatt, C. Finnila et al.· American Journal of Medical...· 0 citations