TLDc proteins: new players in the oxidative stress response and neurological disease

Finelli, Mattéa J.; Oliver, Peter L.

doi:10.1007/s00335-017-9706-7

Cited by 60 publications

(66 citation statements)

References 115 publications

(205 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, TBC1D24 deficiency in Neuro2a cells leads to impaired endocytosis and shorter neurites (Finelli et al, 2019). Pathogenic variants in TBC1D24 (MIM# 613577) are associated with a broad range of nervous system disorders (Finelli & Oliver, 2017;Mucha, Hennekam, Sisodiya, & Campeau, 1993) Azaiez et al, 2014;Mucha et al, 1993;Rehman et al, 2014;Zhang et al, 2014). A genotypephenotype correlation in TBC1D24-related disorders could not yet be established to explain the pleiotropic effects of pathogenic variants in this gene.…”

Section: Discussionmentioning

confidence: 99%

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

et al. 2020

View full text Add to dashboard Cite

The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

show abstract

Section: Discussionmentioning

confidence: 99%

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The OS response is essential for the dynamic balance of reactive oxygen species (ROS), the important intracellular messengers. The imbalance in the numbers of ROS can do harm to DNA, proteins, and lipids and results in neuronal hyperactivity, synaptic dysfunction, and neuronal loss ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

Homozygous TBC1D24 Mutation in a Case of Epilepsia Partialis Continua

Zhou

Lin

et al. 2018

Front. Neurol.

View full text Add to dashboard Cite

TBC1D24 mutation-related epileptic syndrome includes a wide spectrum of epilepsies. We describe a case with a homozygous TBC1D24 mutation inherited from consanguineous parents. The patient manifested epilepsia partialis continua (EPC) and rare secondary generalized tonic–clonic seizure without intellectual disability or developmental delay. EPC, which involved focal limbs, came with waking and went with sleep. The genetic analysis reported a novel mutation in the TBC1D24 gene, c.229_240del (p.82_84del). The homozygous mutation was inherited from her healthy parents who were heterozygous. Morphometric analysis program (MAP), an MRI post-processing technique, was used and detected a subtle abnormality of the brain. A comprehensive analysis based on semiology, electroencephalogram, somatosensory-evoked potential, and MAP suggested a potential focal structural abnormality. This case indicates a possible correlation between the TBC1D24 mutation and brain development abnormality.

show abstract

“…There are five proteins encoded in the human genome that have a TLDc domain and two of them, OXR1 and NCOA7, have been shown to provide an important neuro-protective role against oxidative stress [ 16 ]. It is not known whether human TBC1D24 function in the inner ear or in the hippocampus requires the anti-oxidative function of its TLDc domain [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness

Tona

López

Fenollar–Ferrer

et al. 2020

Genes

View full text Add to dashboard Cite

Human pathogenic variants of TBC1D24 are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human TBC1D24 associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of TBC1D24 c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse Tbc1d24 and human TBC1D24.

show abstract

TLDc proteins: new players in the oxidative stress response and neurological disease

Cited by 60 publications

References 115 publications

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

Homozygous TBC1D24 Mutation in a Case of Epilepsia Partialis Continua

Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness

Contact Info

Product

Resources

About