Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.

BACKGROUND: Variants in the TUBB4A gene are associated with dystonia (DYT-TUBB4A), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and spastic paraplegia. Phenotypes intermediate to these three broad phenotypes are also observed. These are rare disorders, and data from diverse populations remains limited. We report seven Indian cases with dystonia phenotype related to TUBB4A mutation.
METHODS: Among these seven patients, age at onset ranged from 5 to 48 years. Five patients had cranio-cervical onset of dystonia. One patient had prominent parkinsonism with dystonia. Patients responded well to botulinum toxin injected for laryngeal, cervical and jaw dystonia. The patient with parkinsonism responded well to levodopa, albeit with development of dyskinesias. Apart from the common p.Arg2Gly variant in three patients with DYT-TUBB4A, other variants included p.Arg262Pro, p.Arg39Cys and p.Asp245Asn.
CONCLUSIONS: We report the first collection of cases with TUBB4A mutation from India. We expand the phenotype to include levodopa-responsive parkinsonism. Indian patients, consistent with global literature, harbor prominent adductor dysphonia, cervical and jaw dystonia, which responds well to botulinum treatment.

Tubulin beta 4A class IVa (TUBB4A) spectrum disorders include autosomal dominant dystonia type 4 or hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). However, in rare cases, only mild hypomyelination in the cortex with no basal ganglia atrophy may be observed. We report a case of a family with TUBB4A mutation and complicated hereditary spasticity paraplegia (HSP). We performed quadro whole-exome sequencing (WES) on the family to identify the causative gene of progressive spastic paraparesis with isolated hypomyelination leukodystrophy. We identified a novel TUBB4A p.F341L mutation, which was present in all three affected patients but absent in the unaffected father. The affected patients presented with adult-onset TUBB4A disorder, predominant spastic paraparesis with/without ataxia, and brain hypomyelination with no cognitive impairment or extrapyramidal symptoms. In the literature, HSP is considered a TUBB4A spectrum disorder.

暂无摘要。

TUBB4A pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset TUBB4A-related leukodystrophy cohort with existing gross motor outcome tools. Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification System (GMFCS-ER), and Gross Motor Function Classification-Metachromatic Leukodystrophy (GMFC-MLD) were selected through face validity. Subjects with a confirmed clinical and molecular diagnosis of TUBB4A-related leukodystrophy were enrolled. Participants\' sex, age, genotype, and age at disease onset were collected, together with GMFM-88 and concurrent GMFCS-ER and GMFC-MLD. Performances on each measure were compared. GMFM-88 floor effect was defined as total score below 20%. A total of 35 subjects participated. Median performance by GMFM-88 was 16.24% (range 0-97.31), with 42.9% (n = 15) of individuals performing above the floor. GMFM-88 Dimension A (Lying and Rolling) was the best-performing dimension in the GMFM-88 (n = 29 above the floor). All levels of the Classification Scales were represented, with the exception of the GMFC-MLD level 0. Evaluation by GMFM-88 was strongly correlated with the Classification Scales (Spearman correlations: GMFCS-ER:GMFM-88 r = 0.90; GMFC-MLD:GMFM-88 r = 0.88; GMFCS-ER:GMFC-MLD: r = 0.92). Despite overall observation of a floor effect, the GMFM-88 is able to accurately capture the performance of individuals with attenuated phenotypes. GMFM-88 Dimension A shows no floor effect. GMFC-MLD shows a strong correlation with GMFCS-ER and GMFM-88, supporting its use as an age-independent functional score in TUBB4A-related leukodystrophy.

BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare genetic disease due to a TUBB4A mutation, with motor features including dystonia. Deep brain stimulation (DBS) can be used to treat dystonia in pediatric populations, although the response is highly variable and preferential toward specific etiologies.
METHODS: A single pediatric subject with H-ABC received DBS using a staged procedure involving temporary depth electrode placement, identification of optimal stimulation targets, and permanent electrode implantation. After surgery, the patient significantly improved on both the Burke-Fahn-Marsden Dystonia Rating Scale and the Barry-Albright Dystonia Scale. The patient\'s response suggests that DBS can have potential benefit in H-ABC.
CONCLUSIONS: TUBB4A mutations are associated with a variety of clinical phenotypes, and there is a lack of clearly identified targets for DBS, with this case being the second reported instance of DBS in this condition. The staged procedure with temporary depth electrode testing is recommended to identify optimal stimulation targets. The response seen in this patient implies that such a staged procedure may provide benefit in other conditions where DBS targets are currently unknown, including rare genetic or metabolic conditions associated with movement disorders.

Background: Melanoma is one of the most malignant skin carcinomas with high metastatic potential. Increasing evidence has demonstrated that β-tubulin 4A (TUBB4A) plays a key role in the development and progression of several types of human cancer. However, the potential function of TUBB4A in cutaneous melanoma remains to be determined. Methods: We first performed a differential expression analysis based on skin melanoma tissues and normal tissues from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets and then a survival analysis to identify prognostic-related key genes. We further conducted in vitro biochemical experiments to verify the functional roles of the key gene TUBB4A. Two small-molecule inhibitors of TUBB4A, Dihydroartemisinin (DHA) and Nocodazole, were used to validate the effect of TUBB4A on the apoptosis and cell cycle of melanoma cells. Results: We found that TUBB4A expression was positively correlated to the overall survival (OS) of cutaneous melanoma patients. The coexpressed genes with TUBB4A were enriched in melanoma-related pathways and functions. The experimental results showed that knockdown of TUBB4A inhibited the proliferation and migration of A375 and B16-F10 melanoma cells. Moreover, DHA and Nocodazole promoted the apoptosis of melanoma cells and blocked the melanoma tumor cell cycle in the G2/M stage. Conclusion: TUBB4A may be a prognostic biomarker and therapeutic target for melanoma.

OBJECTIVE: Skin cutaneous melanoma(SKCM) is the most severe, and complex disease of all skin cancers. The molecular mechanisms of this cancer progression are not well understood.
METHODS: GEPIA online database was used to validate the differentially expressed genes from two GEO datasets. The prognostic value was calculated by the Kaplan-Meier method. RT-qPCR verified the expression of TUBB4A in SKCM cell line, and the immunohistochemistry of TUBB4A in SKCM and normal skin tissues were gained from Human Protein Atlas. Seven target prediction databases predicted potential microRNAs(miRNAs), and upstream long non-coding RNAs(lncRNAs) were predicted by starBase. The co-expressed gene of TUBB4A was obtained using the two online analysis sites UALCAN and starBase. These co-expressed genes were performed by enrichment analysis, and immune infiltration result was obtained by the TIMER2 online database. The receiver operating characteristic( ROC) curve was applied to evaluate the diagnostic value of TUBB4A in the SKCM and normal skin group. A new nomogram about TUBB4A was constructed to forecast the survival rate of SKCM patients at 1, 3, and 5 years.
RESULTS: Firstly, we found that DLL3 and TUBB4A were significantly higher expressed in skin cutaneous melanoma than normal skin. Subsequently, by analyzing progress-free interval(PFI), diseasespecific survival(DSS), and disease-free survival(DFS), only TUBB4A was the most potent gene for inhibiting shin cutaneous melanoma progression. In gene ontology(GO)/ kyoto encyclopedia of genes and genomes(KEGG) analysis, TUBB4A may play a key role in the progression of skin cutaneous melanoma by regulating mitochondrial function and affecting cellular metabolism, possibly related to the immune infiltration of CD4+Th1 cells and NK cells. The upstream non-coding RNA(ncRNA) acts through the SNHG16-hsa-let-7b-5p-TUBB4A axis.
CONCLUSIONS: In conclusion, we elucidated the regulatory role of the SNHG16-hsa-let-7b-5p-TUBB4A axis in the progression of skin cutaneous melanoma by modulating mitochondrial function to affect cellular metabolism. TUBB4A may be a promising diagnostic biomarker and therapeutic target for cutaneous skin melanoma.

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UNASSIGNED: DYT-TUBB4A, formerly known as DYT4, has not been comprehensively described as only one large family and three individual cases have been published. We have recently described an in depth genetic and protein structural analysis of eleven additional cases from four families with four new pathogenic variants. We aim to report on the phenomenology of these cases suffering from DYT-TUBB4A and to perform a comprehensive review of the clinical presentation and treatment responses of all DYT-TUBB4A cases reported in the literature.
UNASSIGNED: The clinical picture was typically characterized by laryngeal dystonia (more than three quarters of all cases), associated with cervical dystonia, upper limb dystonia and frequent generalization. Extension of the dystonia to the lower limbs, creating the famous \"hobby horse\" gait, was present in more than 20% of cases (in only one of ours). Globus pallidus pars interna (GPi) deep brain stimulation (DBS), performed in 4 cases, led to a good improvement with greatest benefit in motoric and less benefit in laryngeal symptoms. Medical treatment was generally rather poorly effective, except some benefit from propranolol, tetrabenazine and alcohol intake.
UNASSIGNED: Laryngeal involvement is a hallmark of DYT-TUBB4A. Symptomatic treatment with GPi-DBS led to the greatest benefit in motoric symptoms. Nevertheless, TUBB4A mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia and regular screening of TUBB4A mutations for isolated dystonias has a very low yield.