Alternative titles; symbols
HGNC Approved Gene Symbol: TBC1D24
SNOMEDCT: 1231737000, 719800009, 784342008;
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:2,475,127-2,505,730 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Deafness, autosomal dominant 65 | 616044 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 86 | 614617 | Autosomal recessive | 3 | |
| Developmental and epileptic encephalopathy 16 | 615338 | Autosomal recessive | 3 | |
| DOORS syndrome | 220500 | Autosomal recessive | 3 | |
| Epilepsy, rolandic, with paroxysmal exercise-induce dystonia and writer's cramp | 608105 | Autosomal recessive | 3 | |
| Myoclonic epilepsy, infantile, familial | 605021 | Autosomal recessive | 3 |
The TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins, which coordinate Rab proteins and other GTPases for the proper transport of intracellular vesicles (summary by Campeau et al., 2014).
By sequencing clones obtained from a size-fractionated brain cDNA library, followed by RT-PCR, Hirosawa et al. (1999) obtained a cDNA encoding TBC1D24, which they called KIAA1171. The deduced 595-amino acid protein contains a TBC domain, suggesting it is involved in cell signaling. RT-PCR ELISA detected low expression of TBC1D24 in all adult and fetal tissues examined except spleen, which showed no expression. Expression was moderate in amygdala and cerebellum and low in all other adult brain regions examined.
Falace et al. (2010) stated that TBC1D24 encodes a 553-amino acid protein. RT-PCR analysis showed TBC1D24 expression in multiple human tissues, with highest expression in brain, followed by testis, skeletal muscle, heart, kidney, lung, and liver. Tbc1d24 was expressed in the cortex and hippocampus of developing mouse brain, with increased expression during cortical development, particularly in the internal part of the cortical plate and in the subventricular zone.
Corbett et al. (2010) stated that the TBC1D24 protein contains 559 amino acids and contains an N-terminal TBC domain and a C-terminal TLD domain. Alternative splicing can result in as many as 3 isoforms. They demonstrated Tbc1d24 expression in mouse embryonic stem cell-derived neurons, cultured embryonic day-18.5 (E18.5) mouse hippocampal neurons, and developing mouse brain.
Guven and Tolun (2013) used Sanger sequencing and PCR to analyze the structure and expression of 4 different TBC1D24 mRNA isoforms. Isoform 1 encodes a 559-residue protein that includes all 8 exons; isoform 2 encodes a 553-residue protein that lacks exon 3; isoform 3 encodes a 506-residue protein that lacks exon 4; and isoform 4 encodes a 424-residue protein that lacks exon 5 and is coded after exon 4 in a frame different from that of the other isoforms. All isoforms were observed in all brain regions investigated, including the cerebellum, corpus callosum, frontal cortex, occipital cortex, striatum, parietal cortex, and brainstem. In all brain samples, isoform 1 was more abundant than the other isoforms. Of 5 nonneuronal tissues tested, isoform 2 was much more abundant than the total of all other isoforms in liver, blood, adipose tissue, and bone marrow, but was less abundant than other isoforms in skeletal muscle.
Campeau et al. (2014) noted that TBC1D24 is the only TBC/RabGAP with a TLDc domain, which is thought to be involved in oxidative stress resistance.
Campeau et al. (2014) found high expression of the Tbc1d24 gene in chondrocytes of the distal phalanges of the mouse forelimb and in the calvarium of newborn mice.
In the mouse inner ear, Rehman et al. (2014) found expression of the Tbc1d24 gene in spiral ganglion cells, a collection of neurons critical for hearing and balance.
In the developing mouse cochlea, Zhang et al. (2014) and Azaiez et al. (2014) found expression of the Tbc1d24 gene in the stereocilia of inner and outer hair cells as well as in spiral ganglion neurons.
By in situ hybridization of mouse brain, Tona et al. (2019) showed that Tbc1d24 was expressed in the CA1-CA3 region of hippocampus, dentate gyrus, cerebral cortex, and olfactory bulb. Immunotransmission electron microscopy revealed that Tbc1d24 protein localized in the trans-Golgi network and at synapses in mouse hippocampus.
By in situ hybridization and immunostaining, Tona et al. (2020) showed that TBC1D24 was expressed in spiral ganglion neurons in both human and mouse. However, TBC1D24 expression was detected in human hair cells, but not in mouse hair cells.
Uytterhoeven et al. (2011) showed that the Drosophila ortholog of TBC1D24, which they named 'skywalker' (Sky), was widely expressed and abundant in nervous system and at synaptic areas in ventral nerve cord and neuromuscular junction boutons.
Corbett et al. (2010) noted that the TBC1D24 gene contains 7 exons.
A new 18-bp exon 3 was subsequently identified, indicating that the TBC1D24 gene contains 8 exons (summary by Guven and Tolun, 2013).
Gross (2010) mapped the TBC1D24 gene to chromosome 16p13.3 based on an alignment of the TBC1D24 sequence (GenBank AB449911) with the genomic sequence (GRCh37).
By coimmunoprecipitation studies in COS-7 cells, Falace et al. (2010) found that TBC1D24 binds ARF6 (600464), a member of the Ras-related family of small GTPases that regulate exo- and endocytosis. The intensity of the coimmunoprecipitated band increased in the presence of inactive GDP-locked ARF6, indicating a GDP-dependent interaction. Overexpression of TBC1D24 in mouse embryo cortical neurons resulted in a marked increase in neurite length and arborization compared to controls, affecting both axonal and dendritic compartments. The findings were consistent with TBC1D24 acting as a negative regulator of ARF6.
Corbett et al. (2010) found that overexpression of TBC1D24 in mouse E18.5 primary hippocampal neurons resulted in significantly increased length of primary axons and increased numbers of neurite termini at days 5 and 7 posttransfection, consistent with increased arborization. These findings suggested that TBC1D24 has an important role in normal brain development.
Uytterhoeven et al. (2011) found that Drosophila Sky regulated vesicle traffic at synaptic boutons of neurons in a cell-autonomous manner. In Sky mutant neurons, excessive newly internalized synaptic vesicle membrane cycled via intermediate sorting endosomes upon stimulation. Consequently, Sky mutant neurons had increased neurotransmitter release that was facilitated by ESCRT complex-mediated sorting and arose from an enlarged readily releasable pool of synaptic vesicles. The authors identified Sky as a Rab35 GTPase-activating protein, and Rab35 activity was a critical regulator of neurotransmitter release. Further analysis showed that, in Sky mutants, endosomal trafficking mediated more efficient shuttling of ubiquitinated proteins for degradation, leaving more functional synaptic vesicle proteins to populate the readily releasable pool.
By expressing human TBC1D24 with disease-causing mutations in Tbc1d24-knockout Neuro2a mouse neuronal cells, Finelli et al. (2019) found that all mutations tested led to at least a partial loss of TBC1D24 function and influenced neuronal cell differentiation and sensitivity to oxidative stress. Analysis of cultured primary neurons from mice with 1 disrupted Tbc1d24 allele revealed decreased miniature excitatory postsynaptic currents with no effect on excitatory synapse number. Tbc1d24 haploinsufficiency also caused defective endocytosis and increased endosomal volume in primary neurons.
Familial Infantile Myoclonic Epilepsy
In affected members of a large Italian family with familial infantile myoclonic epilepsy (FIME; 605021) mapping to chromosome 16p13.3 (Zara et al., 2000), Falace et al. (2010) identified compound heterozygosity for 2 mutations in the TBC1D24 gene (613577.0001 and 613577.0002) that were shown to decrease function. The identification of these mutations suggested involvement of the ARF6-dependent molecular pathway in the generation of brain hyperexcitability and seizures. The findings also suggested a critical role for TBC1D24 in developmentally regulated events essential for the morphologic and functional maturation of neuronal circuitry, disruption of which likely plays a role in the etiology of epileptic disorders.
By genomewide linkage analysis followed by candidate gene sequencing of a large consanguineous Arab family with seizures and intellectual disability, Corbett et al. (2010) found linkage to chromosome 16p13 and identified a homozygous loss of function mutation in the TBC1D24 gene (F251L; 613577.0003). The findings suggested that TBC1D24 plays an important role in normal human brain development.
Developmental and Epileptic Encephalopathy 16
In affected members of a consanguineous Turkish kindred with developmental and epileptic encephalopathy-16 (DEE16; 615338), previously reported by Duru et al. (2010), Guven and Tolun (2013) identified a homozygous truncating mutation in the TBC1D24 gene (613577.0004). The mutation was predicted to affect isoforms 1, 3, and 4, but not isoform 2, which lacks exon 3. The disorder was characterized by onset of seizures in the first weeks or months of life. Seizures were predominantly myoclonic but also focal, were unresponsive to medication, and occurred frequently. Affected infants showed psychomotor regression or lack of psychomotor development, as well as other neurologic features such as extrapyramidal signs and hypotonia. All died in childhood. Guven and Tolun (2013) noted that the severity of the mutation paralleled the severity of the phenotype in this family.
In 2 sisters with DEE16, Milh et al. (2013) identified compound heterozygosity for 2 mutations in exon 2 of the TBC1D24 gene (F229S, 613577.0005 and C156X, 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family. The patients developed clonic seizures early in the second month of life and thereafter developed prolonged, almost continuous seizures of different types with severe neurologic deterioration and lack of psychomotor development. The clinical diagnosis was consistent with malignant migrating partial seizures of infancy (MMPSI). Screening of the TBC1D24 gene in 8 additional MMPSI patients did not identify any mutations.
By exome sequencing in a 16-month-old Japanese girl with DEE, Nakashima et al. (2019) identified a homozygous missense mutation in the TBC1D24 gene (E148K; 613577.0019). Sanger sequencing showed that her mother was heterozygous for the variant, but her father had only wildtype alleles. An analysis of loss-of-heterozygosity (LOH) showed an approximately 11-Mb LOH region encompassing TBC1D24. Analysis of variants in the region was consistent with maternal segmental uniparental disomy of chromosome 16.
Deafness, Onychodystrophy, Osteodystrophy, Impaired Intellectual Development, and Seizures Syndrome
In affected individuals from 9 unrelated families with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500), Campeau et al. (2014) identified homozygous or compound heterozygous mutations in the TBC1D24 gene (see, e.g., 613577.0007-613577.0011). The mutations in the first families were found by whole-exome sequencing and confirmed by Sanger sequencing. Most of the mutations were missense substitutions; functional studies were not performed. The 9 families were ascertained from a larger cohort of 26 families with clinical features suggestive of the disorder. The remaining families did not carry TBC1D24 mutations, indicating genetic heterogeneity.
Autosomal Recessive Deafness 86
In affected members of 4 consanguineous Pakistani families with autosomal recessive deafness-86 (DFNB86; 614617), including the family reported by Ali et al. (2012), Rehman et al. (2014) identified 2 different homozygous missense mutations in the TBC1D24 gene (D70Y, 613577.0012 and R293P, 613577.0013). The mutations were found using a combination of linkage analysis and whole-exome sequencing. Functional studies of the variants were not performed. Detailed analysis of 2 of the families revealed that seizures did not segregate with deafness.
Autosomal Dominant Deafness 65
Simultaneously and independently, Zhang et al. (2014) and Azaiez et al. (2014) identified the same heterozygous missense mutation in the TBC1D24 gene (S178L; 613577.0014) in affected members of a Han Chinese family and a European family, respectively, with autosomal dominant deafness-65 (DFNA65; 616044). The mutations, which were found using a combination of mapping and whole-exome sequencing, were confirmed by Sanger sequencing, and segregated with the disorder in each family. Functional studies were not performed; however, in the developing mouse cochlea, Tbc1d24 was found to be expressed in the stereocilia of inner and outer hair cells as well as in spiral ganglion neurons. Zhang et al. (2014) suggested that the mutation resulted in a gain of function or a dominant-negative effect.
Rolandic Epilepsy with Paroxysmal Exercise-Induced Dystonia and Writer's Cramp
In 3 members of a consanguineous Italian family with Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC; 608105), Luthy et al. (2019) identified compound heterozygous missense mutations in the TBC1D24 gene (G501R, 613577.0015 and R360H, 613577.0016). The mutations, which were found by sequencing of the critical region identified by linkage analysis (Guerrini et al., 1999), segregated with the disorder in the family. Three additional patients, including 2 unrelated patients of Han Chinese origin, with sporadic occurrence of the disorder were found to carry compound heterozygous mutations (see, e.g., 613577.0017 and 613577.0018) through whole-exome sequencing. All the patients had biallelic mutations that could be described as hypomorphic mutations affecting the TBC domain, which is important for the regulation of vesicular membrane trafficking at synapses, or a mutation with a mild effect on protein function (R360H), coupled with missense mutations that severely affect the TLDc domain, which is the catalytic domain and thought to be involved in oxidative stress resistance. Studies of patient cells were not performed, but detailed structural analysis predicted that the mutations may have variable destabilizing effects on the protein. In vivo studies in Drosophila demonstrated that the G501R TLDc mutation caused activity-induced locomotion and synaptic vesicle trafficking defects, while R360H was comparatively benign. The neuronal phenotypes of the G501R mutation were consistent with exacerbated oxidative stress sensitivity, which could be rescued by treatment with antioxidants that restored synaptic vesicle trafficking levels and sustained behavioral activity. The authors suggested that the TBC1D24 TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies.
Finelli et al. (2019) found that mice with 1 disrupted Tbc1d24 allele had normal growth, behavior, gross brain structure, neuronal migration, and auditory function. However, haploinsufficiency for Tbc1d24 had a clear impact on maturation and oxidative stress resistance of neurons in mutant mice.
Tona et al. (2019) found that mice homozygous for a frameshift mutation at ser324 of Tbc1d24, which was identical to the human mutation (613577.0004) associated with early infantile epileptic encephalopathy (DEE16; 615338), exhibited spontaneous seizures and died by 3 weeks of age, resembling the human phenotype. Mutant mice also showed high-velocity wild running that was associated with seizures rather than auditory or vestibular defects. Wildtype mice express 2 Tbc1d24 splice variants that encode a short and a long isoform in neural tissues. Expression of the variants revealed a postnatal switch from the short isoform to the long isoform, as predominant expression of the short isoform during embryonic and early postnatal development switched to expression of the long isoform later in development. The frameshift mutation only affected the long variant, and as a result, the wildtype short isoform was still expressed in mutant mice, whereas the long isoform was not. In mutant mice, expression of the short isoform increased dramatically in brain during early postnatal development a few days before abrupt onset of seizures, implying that lack of the long isoform may have been related to onset of seizures. Further analysis identified Srrm3 as a regulator of Tbc1d24 alternative splicing in mouse brain, with Srrm3 supporting generation of the variant encoding the long isoform. Tbc1d24 was not spliced in mouse inner ear to generate the long isoform, providing a possible explanation as to why mice with the frameshift mutation had normal hearing.
Tona et al. (2020) generated mouse models for the human TBC1D24 mutations asp70 to tyr (D70Y; 613577.0012) and ser178 to leu (S178L; 613577.0014) associated with nonsyndromic deafness DFNB86 (614617) and DFNA65 (616044), respectively. Unlike their corresponding human phenotypes, mice with the D70Y or S178L mutation in Tbc1d24 did not have hearing loss. The authors also generated mice compound heterozygous for the Ser324ThrfsTer3 (613577.0004) and His336GlnfsTer12 (613577.0010) Tbc1d24 mutations as a model for human syndromic deafness and found that these mutant mice recapitulated the human seizure phenotype but had normal hearing. Modeling of mouse and human TBC1D24 suggested that deafness arising from the TBC1D24 D70Y mutation in human, but not in mouse, is related to evolutionary divergence in functional necessity and cell type-specific regulation of expression of human TBC1D24 compared with mouse Tbc1d24. In contrast, the S178L mutation had a stabilizing effect on the Tbc1d24 protein in mouse, but not in human, providing a possible explanation for the phenotypic differences in mice and humans with this TBC1D24 mutation.
In affected members of a large Italian family with infantile myoclonic epilepsy (FIME; 605021) mapping to chromosome 16p13.3 (Zara et al., 2000), Falace et al. (2010) identified compound heterozygosity for 2 mutations in the TBC1D24 gene: a 439G-C transversion in exon 2, resulting in an asp147-to-his (D147H) substitution in the TBC domain, and a 1526C-T transition in exon 7, resulting in an ala509-to-val (A509V) substitution in the TLD domain. Neither mutation was found in 300 Italian controls. Affected individuals had myoclonic epilepsy that started in early infancy as myoclonic seizures, febrile convulsions, and tonic-clonic seizures, with normal mental and neurologic development. In vitro studies in COS-7 cells showed that the D147H mutant impaired normal interaction with ARF6 (600464), and that A509V mutant severely affected ARF6-dependent TBC1D24 function without affecting the interaction. Overexpression of wildtype TBC1D24 in mouse embryonic cortical cells resulted in an increase in neurite length and branching, whereas expression of the FIME-associated mutations significantly reverted this phenotype, showing a partial (D147H) or complete (A509V) loss of function.
For discussion of the ala509-to-val (A509V) mutation in the TBC1D24 gene that was found in compound heterozygous state in patients with familial infantile myoclonic epilepsy (FIME; 605021) by Falace et al. (2010), see 613577.0001.
In affected members of a consanguineous Arab family with infantile myoclonic epilepsy (FIME; 605021) and intellectual disability in some, Corbett et al. (2010) identified a homozygous 751T-C transition in exon 2 of the TBC1D24 gene, resulting in a phe251-to-leu (F251L) substitution within the TBC domain. The mutation occurred in a highly conserved residue and was not found in 210 ethnically matched control chromosomes. Overexpression of wildtype TBC1D24 in mouse E18.5 primary hippocampal neurons resulted in increased arborization, whereas overexpression of the F251L mutant was no different than control, consistent with a loss of function.
In affected members of a consanguineous Turkish kindred with developmental and epileptic encephalopathy-16 (DEE16; 615338) previously reported by Duru et al. (2010), Guven and Tolun (2013) identified a homozygous 2-bp deletion (c.969delGT) in exon 3 of the TBC1D24 gene, resulting in a frameshift and premature termination (Ser324ThrfsTer3), yielding a protein 42% shorter than the native protein. The mutation segregated with the disorder and was not found in 120 control samples. The mutation was predicted to affect isoforms 1, 3, and 4, but not isoform 2, which lacks exon 3. Guven and Tolun (2013) noted that the severity of the mutation paralleled the severity of the phenotype in this family.
In 2 sisters with developmental and epileptic encephalopathy-16 (DEE16; 615338), Milh et al. (2013) identified compound heterozygosity for 2 mutations in exon 2 of the TBC1D24 gene: a c.686T-C transition, resulting in a phe229-to-ser (F229S) substitution at a highly conserved residue in the TBC domain, and c.468C-A transversion, resulting in a cys156-to-ter substitution (C156X; 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family. The patients developed clonic seizures early in the second month of life and thereafter developed prolonged, almost continuous seizures of different types with severe neurologic deterioration and lack of psychomotor development. The clinical diagnosis was consistent with malignant migrating partial seizures of infancy (MMPSI). Coimmunoprecipitation studies showed that the F229S mutation impaired the interaction of TBC1D24 with ARF6 (600464), and overexpression of the mutant protein in primary cortical neurons abolished the ability of TBC1D24 to increase neurite length and arborization, consistent with a loss of function.
For discussion of the cys156-to-ter (C156X) mutation in the TBC1D24 gene that was found in compound heterozygous state in patients with developmental and epileptic encephalopathy-16 (DEE16; 615338) by Milh et al. (2013), see 613577.0005.
In 4 affected individuals from 3 unrelated families with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500), Campeau et al. (2014) identified a homozygous c.724C-T transition in the TBC1D24 gene, resulting in an arg242-to-cys (R242C) substitution. The families were from the United States, India, and Brazil. Three affected individuals from 2 additional families were compound heterozygous for R242C and another mutation in the TBC1D24 gene: R40C (613577.0008) or Q20E (613577.0009). The mutations in the first families were found by whole-exome sequencing and confirmed by Sanger sequencing. All substitutions occurred at conserved residues and were not found in the Exome Variant Server database.
In a Japanese patient with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500), Campeau et al. (2014) identified compound heterozygous mutations in the TBC1D24 gene: a c.118C-T transition, resulting in an arg40-to-cys (R40C) substitution, and R242C (613577.0007). Both substitutions occurred at conserved residues and were not present in the Exome Variant Server database.
In 2 sibs from Chile with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500), Campeau et al. (2014) identified compound heterozygous mutations in the TBC1D24 gene: a c.58C-G transversion, in a gln20-to-glu (Q20E) substitution, and R242C (613577.0007). Both substitutions occurred at conserved residues and were not present in the Exome Variant Server database.
In a German patient with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500), Campeau et al. (2014) identified compound heterozygosity for 2 mutations in the TBC1D24 gene: a 1-bp deletion (c.1008delT), resulting in a frameshift and premature termination (His336GlnfsTer12), and a splice site mutation in intron 5 (c.1206+5G-A; 613577.0011). The heterozygous c.1008delT mutation was found in 2 of 6,118 individuals in the Exome Variant Server. Fibroblasts from this patient showed 5% TBC1D24 mRNA and no detectable protein compared to controls, consistent with a loss of function. An unrelated French patient was heterozygous for the c.1008delT mutation, but a second mutation was not identified.
For discussion of the splice site mutation in the TBC1D24 gene (c.1206+5G-A) that was found in compound heterozygous state in a patient with deafness, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (DOORS; 220500) by Campeau et al. (2014), see 613577.0010.
In affected members of 3 consanguineous Pakistani families with autosomal recessive deafness-86 (DFNB86; 614617), including the family reported by Ali et al. (2012), Rehman et al. (2014) identified a homozygous c.208G-T transversion in the TBC1D24 gene, resulting in an asp70-to-tyr (D70Y) substitution at a highly conserved residue in the TBC domain. The mutation was found using a combination of linkage analysis and whole-exome sequencing, and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the families and was not present in the Exome Variant Server or 1000 Genomes Project databases or in 634 control chromosomes. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed.
In affected members of a consanguineous Pakistani family with autosomal recessive deafness-86 (DFNB86; 614617), Rehman et al. (2014) identified a homozygous c.878G-C transversion in the TBC1D24 gene, resulting in an arg293-to-pro (R293P) substitution at a highly conserved residue. The mutation was found using a combination of linkage analysis and whole-exome sequencing, and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not present in the Exome Variant Server or 1000 Genomes Project databases or in 634 control chromosomes. Functional studies of the variant were not performed.
In affected members of a Han Chinese family and a European family, respectively, with autosomal dominant deafness-65 (DFNA65; 616044), Zhang et al. (2014) and Azaiez et al. (2014) identified the same heterozygous c.533C-T transition in the TBC1D24 gene, resulting in a ser178-to-leu (S178L) substitution at a highly conserved residue. The mutation, which was found using a combination of mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in each family. It was not found in the 1000 Genomes Project or Exome Variant Server databases, in 1,000 Han Chinese controls, or in 300 CEPH controls. Functional studies of the variant were not performed. Zhang et al. (2014) suggested that the mutation resulted in a gain of function or a dominant-negative effect.
In 3 members of a consanguineous Italian family with Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC; 608105), Luthy et al. (2019) identified compound heterozygous missense mutations in the TBC1D24 gene: a c.1501G-A transition (c.1501G-A, NM_001199107.1), resulting in a gly501-to-arg (G501R) substitution, and a c.1079G-A transition, resulting in an arg360-to-his (R360H; 613577.0016) substitution. The mutations, which were found by sequencing of the critical region identified by linkage analysis (Guerrini et al., 1999), segregated with the disorder in the family. The c.1501G-A variant was not found in the gnomAD database, whereas c.1079G-A was found at a low frequency (4 of 267,568 alleles). Both mutations occurred at conserved residues in the TLDc catalytic domain.
For discussion of the c.1079G-A transition (c.1079G-A, NM_001199107.1) in the TBC1D24 gene, resulting in an arg360-to-his (R360H) substitution, that was found in compound heterozygous state in a family with Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC; 608105) by Luthy et al. (2019), see 613577.0015.
In 2 unrelated patients (patients 5 and 6) of Han Chinese descent with Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC; 608105), Luthy et al. (2019) identified compound heterozygous mutations in the TBC1D24 gene: a 12-bp deletion (c.241_252del, NM_001199107.1), resulting in an in-frame deletion in the TBC domain, (Ile81_Lys84del), and a c.1499C-T transition, resulting in an ala500-to-val (A500V; 613577.0018) substitution at a conserved residue in the TLDc domain. The mutations were found by whole-exome sequencing in both patients. The mutations were confirmed by Sanger sequencing in patient 5 and demonstrated to be inherited from the unaffected parents, confirming segregation. The in-frame deletion was found among individuals of East Asian descent (frequency of 1.2 x 10(-3)); the A500V variant was very rare in control databases. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.1499C-T transition (c.1499C-T, NM_001199107.1) in the TBC1D24 gene, resulting in an ala500-to-val (A500V) substitution, that was found in compound heterozygous state in 2 patients with Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC; 608105) by Luthy et al. (2019), see 613577.0017.
By exome sequencing in a 16-month-old Japanese girl with developmental and epileptic encephalopathy-16 (DEE16; 615338), Nakashima et al. (2019) identified a homozygous c.442G-A transition in the TBC1D24 gene, resulting in a glu148-to-lys (E48K) substitution. Sanger sequencing showed that her mother was heterozygous for the variant, whereas her father had only wildtype alleles. An analysis of loss-of-heterozygosity (LOH) showed an approximately 11-Mb LOH region encompassing TBC1D24. Analysis of the variants in the region was consistent with maternal segmental uniparental disomy of chromosome 16. The c.442G-A variant was rare in the gnomAD database, being present in only 2 of 242,430 alleles.
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