Alternative titles; symbols
HGNC Approved Gene Symbol: DEPDC5
Cytogenetic location: 22q12.2-q12.3 Genomic coordinates (GRCh38) : 22:31,753,968-31,908,033 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.2-q12.3 | Developmental and epileptic encephalopathy 111 | 620504 | Autosomal recessive | 3 |
| Epilepsy, familial focal, with variable foci 1 | 604364 | Autosomal dominant | 3 |
The DEPDC5 gene encodes a GTPase that, together with NPRL2 (607072) and NPRL3 (600928), constitutes the GATOR1 complex, which inhibits RAG (see, e.g., RRAGA, 612194)-dependent activation of the mTOR signaling pathway (see 601231) that is involved in multiple biologic processes, including cell growth, proliferation, and protein synthesis (summary by van Kranenburg et al., 2015; Liu et al., 2020; Samanta, 2022; Ververi et al., 2023).
By screening cDNA libraries for genes encoding large proteins expressed in brain, Ishikawa et al. (1998) isolated DEPDC5, which they called KIAA0645. The predicted protein contains 1,572 amino acids. RT-PCR analysis detected ubiquitous expression in human tissues.
Using RT-PCR, Dibbens et al. (2013) found expression of the Depdc5 gene at low levels in all mouse brain regions analyzed. Expression occurred throughout brain development, including in midgestation embryonic head, neonatal brain, and whole adult brain. Immunofluorescence studies showed that Depdc5 was expressed in neurons and GABAergic interneurons, but was absent in nonneuronal cells, including astrocytes. Immunofluorescence was localized to the cytosol of the neuronal cell body and was mostly perinuclear, with little or no extension into neuronal processes. This subcellular localization was confirmed in human neurospheres derived from induced pluripotent stem cells from control individuals and in human neuroblastoma cells. These results suggested a role for DEPDC5 in neuronal signal transduction.
Miki et al. (2011) reported that the DEPDC5 gene contains 42 exons.
Cryoelectron Microscopy
Shen et al. (2018) used cryoelectron microscopy to solve structures of GATOR1 and GATOR1-RAG GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 (607072) links DEPDC5 and NPRL3 (600928), and DEPDC5 contacts the RAG GTPase heterodimer. Biochemical analyses revealed that this GATOR1-RAG GTPases structure is inhibitory, and that at least 2 binding modes must exist between the RAG GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA (612194) inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity.
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the KIAA0645 gene to chromosome 22. Miki et al. (2011) stated that the DEPDC5 gene maps to chromosome 22q12.2-q12.3 between the C22ORF30 and YWHAH (113508) genes.
Bar-Peled et al. (2013) identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see 601231). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5, NPRL2 (607072), and NPRL3 (600928) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS (615359), WDR24 (620307), WDR59 (617418), SEH1L (609263), and SEC13 (600152) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA (612194) and RAGB (300725), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, Bar-Peled et al. (2013) concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer.
Using HEK293 cells, Gu et al. (2017) found that SAMTOR (BMT2; 617855) bound the GATOR1-KICSTOR (see 617420) supercomplex, and that SAMTOR-GATOR1-KICSTOR inhibited MTORC1 signaling at lysosomes. Binding of S-adenosylmethionine (SAM) to SAMTOR interfered with binding of SAMTOR to GATOR1-KICSTOR and permitted MTORC1 signaling. Methionine starvation reduced SAM levels, promoting association of SAMTOR with GATOR1-KICSTOR and inhibition of MTORC1 lysosomal signaling. The authors concluded that SAMTOR senses methionine availability via SAM binding and thereby links methionine availability with MTORC1 signaling.
Chen et al. (2018) found that DEPDC5 underwent proteasome-mediated degradation in response to amino acid stimulation. The authors identified CUL3 (603136)-RBX1 (603814)-KLHL22 (618020) as the E3 ubiquitin ligase that catalyzed lys48-linked polyubiquitination at multiple sites of DEPDC5, a key step in DEPDC5 degradation. During amino acid starvation, KLHL22 was trapped by 14-3-3 proteins (see 601289) in the nucleus. Upon amino acid stimulation, KLHL22 was released and translocated to the cytosol, where it localized, at least in part, to the lysosome, where GATOR1 resides. KLHL22 played an essential role in amino acid-induced activation of mTORC1 and its downstream signaling events, and functional studies showed that this role was evolutionarily conserved from worms through mammals.
Familial Focal Epilepsy With Variable Foci 1
In affected members of 7 of 8 families with autosomal dominant familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Dibbens et al. (2013) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0001-614191.0004). The first 2 mutations were found by exome sequencing, and mutations occurred throughout the gene. Screening of this gene in 82 probands with focal epilepsy and no detectable structural lesions identified pathogenic DEPDC5 mutations in 10 (12.2%), indicating that mutations in this gene are an important cause of the disorder. Most mutations caused premature termination of the protein, suggesting haploinsufficiency as the disease mechanism. Most patients had onset in the first or second decades of temporal or frontal lobe epilepsy. Parietal, occipital, and multifocal seizures were less common. All families showed some degree of incomplete penetrance.
In affected members of 6 (37%) of 16 families with autosomal dominant focal epilepsies, Ishida et al. (2013) identified 6 different heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0005-614191.0007). Five of the mutations resulted in a truncated protein, indicating that haploinsufficiency is the disease mechanism. Four families had FFEVF1, 2 had features consistent with temporal lobe epilepsy, and 1 had features consistent with nocturnal frontal lobe epilepsy; all types of focal seizures.
In 9 patients from 4 unrelated families of European descent with FFEVF1 presenting as autosomal dominant nocturnal frontal lobe epilepsy, Picard et al. (2014) identified 4 different heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0004; 614191.0008-614191.0009). Functional studies of the variants were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism.
Martin et al. (2014) identified 2 different heterozygous mutations in the DEPDC5 gene (R843X, 614191.0010 and T864M, 614191.0011) in 4 (5%) of 79 French Canadian probands with focal epilepsy. Haplotype analysis was consistent with a founder effect for the R843X mutation. Functional studies were not performed. Martin et al. (2014) noted that Dibbens et al. (2013) had previously identified the R843X mutation in a French Canadian family with the disorder.
Baulac et al. (2015) found that 1 of the patients in an FFEVF1 family reported by Ishida et al. (2013) who had a germline heterozygous R239X mutation in the DEPDC5 gene (614191.0006) also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed focal cortical dysplasia type I (FCD I) with a disturbance of cortical lamination. Baulac et al. (2015) suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. Baulac et al. (2015) identified this individual as patient 1/IV-9.
In 6 affected members of a French-Canadian family with FFEVF1, Nascimento et al. (2015) identified a heterozygous nonsense mutation in the DEPDC5 gene (Q216X; 614191.0015). The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Affected individuals had focal seizures, absence seizures, generalized tonic-clonic seizures, and febrile seizures. Of note, 2 family members who were not sequenced, died of sudden unexpected death in epilepsy (SUDEP) at 58 and 50 years of age. Functional studies of the variant and studies of patient cells were not performed.
In a 6-year-old child with FFEVF1 and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a heterozygous germline nonsense mutation in the DEPDC5 gene (R286X; 614191.0013). The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous nonsense mutation (Q289X) in the DEPDC5 that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR (601231) activity.
In 10 individuals from 7 unrelated Han Chinese families with FFEVF1, Liu et al. (2020) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0006 and 614191.0014). The mutations were found by sequencing of a targeted gene panel and confirmed by Sanger sequencing. Three families (families A-C) carried truncating mutations (2 nonsense and 1 frameshift), and family D carried a termination extension mutation, all of which were absent from gnomAD and predicted to result in functional haploinsufficiency. Studies of patient cells were not performed. Three families carried missense variants (Y7C, Y836C, and G1545S) that were present at low frequencies in public databases and were considered to be variants of uncertain significance (VUS). Of the whole cohort, 6 patients had focal epilepsy with febrile seizures-plus (FEFS+), 1 had febrile seizures, and 3 had focal or unclassified epilepsy. Four unaffected parents carried the variants, indicating incomplete penetrance. In addition, 8 individuals from 4 families (families G-J) with FEFS+, febrile seizures, or rolandic epilepsy, carried a heterozygous P1031H missense variant, and 1 patient (family K) with frontal lobe epilepsy with focal cortical dysplasia carried a homozygous P1031H variant. However, the authors noted that the pathogenicity of the P1031H variant is unclear, and has been classified as a VUS or likely benign. The 12 probands were ascertained from a cohort of 305 patients with focal epilepsy, with DEPDC5 variants accounting for 3.9%. The findings expanded the phenotype of FFEVF1 to include febrile seizures and FEFS+.
Developmental And Epileptic Encephalopathy 111
In 9 patients from 5 unrelated families with developmental and epileptic encephalopathy-111 (DEE111; 620504), Ververi et al. (2023) identified homozygous missense mutations in the DEPDC5 gene: T337R (614191.0016) and R806C (614191.0017). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. Molecular modeling predicted that the mutations would result in a loss of protein stability and adversely affect protein function. Functional studies of the variants were not performed, but immunohistochemical studies of a skin sample from 1 of the patients with the T337R mutation was consistent with an overall increase in mTOR (601231) activity. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that these missense mutations resulted in a partial loss of function.
Hepatitis C Infection
Using a genomewide-association study of 212 Japanese individuals with chronic hepatitis C virus (HCV; see 609532) infection and hepatocellular carcinoma (HCC; 114550) and 765 Japanese individuals with chronic HCV infection without HCC, Miki et al. (2011) identified an intronic SNP in the DEPDC5 gene, rs1012068, that was associated with HCC risk. They confirmed the association using an independent case-control study of 710 cases and 1,625 controls. The association was significant when the 2 stages were analyzed separately as well as together (P combined = 1.27 x 10(-13); odds ratio = 1.75), and the significance level increased further after adjusting for gender, age, and platelet count (P = 1.35 x 10(-14); odds ratio = 1.96). The risk associated with the SNP was weaker in females and those over age 65. RT-PCR analysis of 43 individuals with HCV and HCC revealed higher DEPDC5 expression in tumor than in nontumor tissue, regardless of SNP genotype. Miki et al. (2011) concluded that the intronic SNP rs1012068 is associated with a 2-fold increased risk in HCV-related HCC development.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human DEPDC5 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Marsan et al. (2016) found that Depdc5 -/- rats underwent embryonic lethality that was preceded by global growth delay. Livers of Depdc5 -/- rats contained apoptotic cells, and the cerebral neocortex showed structural defects. Growth delay and embryonic lethality were rescued by prenatal administration of the mTorc1 inhibitor rapamycin. Western blot analysis showed constitutive activation of mTorc1 in brains of Depdc5 -/- embryos. Amino acid starvation in cultured Depdc5 -/- primary rat embryonic fibroblasts led to mTorc1 upregulation, suggesting that DEPDC5 is necessary to control cell growth by repressing the mTORC1 pathway during amino acid starvation. Depdc5 +/- rats displayed no differences in gross anatomy, fertility, and rate of weight gain compared with wildtype, but they had enhanced cell size and dysmorphy of neurons, which were prevented by rapamycin treatment. Moreover, Depdc5 +/- rats showed changes in pyramidal cell electrophysiology, as Depdc5 deficiency impacted both the overall intrinsic properties and excitability of cortical pyramidal neurons.
Hu et al. (2018) found that deletion of Depdc5 in rat brain led to focal cortical mTor hyperactivation. Mutant rats developed spontaneous seizures with focal pathologic and electroclinical features clinically relevant to human FCD IIA (607341).
In affected members of a large Australian family with autosomal dominant familial focal epilepsy with variable foci-1 (FFEVF1; 604364), originally reported by Scheffer et al. (1998) and later by Klein et al. (2012), Dibbens et al. (2013) identified a heterozygous c.21C-G transversion in the DEPDC5 gene, resulting in a tyr7-to-ter (Y7X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance.
In affected members of a Dutch family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), originally reported by Callenbach et al. (2003), Dibbens et al. (2013) identified a heterozygous c.1663C-T transition in the DEPDC5 gene, resulting in an arg555-to-ter (R555X) substitution. The mutation, which was found by exome sequencing, segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance.
In affected members of 3 large French Canadian families with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), originally reported by Xiong et al. (1999) and Berkovic et al. (2004), Dibbens et al. (2013) identified a heterozygous 3-bp in-frame deletion (c.488_490delTGT), resulting in the deletion of phe164 (phe164del). Haplotype analysis indicated a founder effect. The mutation segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance.
In affected members of a large Spanish family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364) reported by Berkovic et al. (2004), Dibbens et al. (2013) identified a heterozygous c.4107G-A transition in the DEPDC5 gene, resulting in a trp1369-to-ter (W1369X) substitution. The mutation segregated with the disorder and was not found in a large exome database or in 710 control chromosomes. However, there was evidence of incomplete penetrance.
Picard et al. (2014) identified the W1369X mutation in 3 members of a family of European descent with FFEVF1 presenting as nocturnal frontal lobe epilepsy.
In affected members of a large French family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), reported as 'family N' by Picard et al. (2000), Ishida et al. (2013) identified a heterozygous 1-bp deletion (c.1122delA) in exon 16 of the DEPDC5 gene, resulting in a frameshift and premature termination (Leu374PhefsTer30). The mutation, which was found by exome sequencing and segregated with the disorder, was not found in several large control databases. Disease penetrance was incomplete.
In affected members of a large French family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), reported as 'family S' by Picard et al. (2000), Ishida et al. (2013) identified a heterozygous c.715C-T transition in exon 12 of the DEPDC5 gene, resulting in an arg239-to-ter (R239X) substitution. The mutation was not found in several large control databases. The mutation was shown to cause nonsense-mediated mRNA decay, indicating that haploinsufficiency is the disease mechanism. Disease penetrance was incomplete.
Baulac et al. (2015) found that 1 of the patients in the family reported by Ishida et al. (2013) who had a germline R239X mutation in the DEPDC5 gene also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed focal cortical dysplasia type I (FCD I) with a disturbance of cortical lamination. Baulac et al. (2015) suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. Baulac et al. (2015) identified this individual as patient 1/IV-9.
In a 17-year-old Han Chinese boy (family B) with FFEVF1, Liu et al. (2020) identified a de novo heterozygous R239X mutation in the DEPDC5 gene. The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in functional haploinsufficiency. The patient had onset of febrile and afebrile generalized tonic-clonic seizures at 15 years of age. Brain imaging was not performed. He became seizure-free on medication.
In affected members of a family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Ishida et al. (2013) identified a heterozygous c.982C-T transition in exon 15 of the DEPDC5 gene, resulting in an arg328-to-ter (R328X) substitution. The mutation was not found in several large control databases.
In 2 affected members of a family of European descent with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Picard et al. (2014) identified a heterozygous c.3259C-T transition in the DEPDC5 gene, resulting in an arg1087-to-ter (R1087X) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient lymphoblasts showed no mutant mRNA, suggesting nonsense-mediated mRNA decay. One mutation carrier was unaffected, consistent with incomplete penetrance. The patients had onset of drug-resistant nocturnal frontal lobe epilepsy and rare diurnal seizures in their teenage years. Functional studies of the variant were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism.
In 2 affected members of a family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Picard et al. (2014) identified a heterozygous c.1459C-T transition in the DEPDC5 gene, resulting in an arg487-to-ter (R487X) substitution. The mutation, which was found by direct sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient lymphoblasts showed no mutant mRNA, suggesting nonsense-mediated mRNA decay. One mutation carrier was unaffected, consistent with incomplete penetrance. The patients had onset of drug-resistant nocturnal frontal lobe epilepsy in early childhood; both also had rare diurnal seizures and intellectual disability. Functional studies of the variant were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism.
In affected members from 3 families with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Martin et al. (2014) identified a heterozygous c.2527C-T transition in exon 28 of the DEPDC5 gene, resulting in an arg843-to-ter (R843X) substitution. One large family contained 11 mutation carriers, including 5 affected, 1 with febrile seizures, and 5 asymptomatic, consistent with incomplete penetrance. All 3 families originated from the same region in Quebec, Canada, and haplotype analysis indicated a founder effect.
In a French Canadian patient with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Martin et al. (2014) identified a heterozygous c.2591C-T transition in exon 28 of the DEPDC5 gene, resulting in a thr864-to-met (T864M) substitution at a highly conserved residue. The variant was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. The only family member available for study was the patient's father, who did not carry the variant. Functional studies were not performed.
In 6 affected members of an Australian family (family A) with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Scheffer et al. (2014) identified a heterozygous c.418C-T transition in the DEPDC5 gene, resulting in a gln140-to-ter (Q140X) substitution, predicted to result in a loss of function and thus haploinsufficiency. The mutation, which was found by whole-exome sequencing, was not present in the dbSNP or Exome Variant Server databases. There were 4 unaffected mutation carriers, consistent with incomplete penetrance. The patients had onset of frontal lobe epilepsy in the first 2 decades; brain imaging in 2 patients showed cortical thickening and loss of gray-white differentiation at the bottom of an abnormal sulcus, suggesting cortical dysplasia.
In a 6-year-old child with familial focal epilepsy with variable foci-1 (FFEVF1; 604364) and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a heterozygous germline c.856C-T transition (c.856C-T, NM_001242896) in the DEPDC5 gene, resulting in an arg286-to-ter (R286X) substitution. The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous c.865C-T transition in the DEPDC5 gene, resulting in a gln289-to-ter (Q289X) substitution that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR (601231) activity. Ribierre et al. (2018) found that mouse embryos with focal mosaic knockdown of the Depdc5 gene in postmitotic neurons, generated by in utero electrocorporation and CRISPR/Cas9 gene editing, demonstrated impaired neuronal radial migration to the cortical plate. The mutant neurons were round and balloon-like, similar to dysmorphic neurons found in focal cortical dysplasia IIa. These abnormalities were associated with increased mTOR activity, and the neuronal migration defects could be prevented by treatment with the mTOR inhibitor rapamycin. Focal mosaic mutant mice showed increased susceptibility to focal seizures, and some showed seizure-related death, reminiscent of sudden expected death in epilepsy (SUDEP). Pyramidal cells from mutant mice showed increased complexity of dendritic branching, hypertrophy of dendritic spins, and enhanced excitatory synaptic activity compared to controls. These findings indicated that complete inactivation of Depdc5 during brain development causes epilepsy with focal cortical malformations, and that biallelic DEPDC5 mutations, germline and brain somatic mosaic (representing Knudson's 2-hit hypothesis of disease mechanism), underlie the focal cortical dysplasia that is sometimes observed in this disorder.
In a 24-year-old Han Chinese woman (family A) with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Liu et al. (2020) identified a heterozygous 1-bp deletion (c.450delG, NM_001242896.1) in the DEPDC5 gene, resulting in a frameshift and premature termination (Val151SerfsTer27). The mutation, which was found by targeted sequencing of a gene panel and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was inherited from the unaffected father, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in functional haploinsufficiency. The patient had onset of seizures at 4 years of age; she had both febrile generalized tonic-clonic seizures and simple partial seizures. EEG showed focal spikes and waves, and brain imaging was normal. She became seizure-free on medication.
In 6 affected members of a French-Canadian family with familial focal epilepsy with variable foci-1 (FFEVF1; 604364), Nascimento et al. (2015) identified a heterozygous c.646C-T transition (c.646C-T, ENST00000536766) in the DEPDC5 gene, resulting in a gln216-to-ter (Q216X) substitution. The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Affected individuals had focal seizures, absence seizures, generalized tonic-clonic seizures, and febrile seizures. Of note, 2 family members who were not sequenced died of sudden unexpected death in epilepsy (SUDEP) at 58 and 50 years of age. Functional studies of the variant and studies of patient cells were not performed.
In 6 patients from 3 unrelated families (families 1-3), all of Irish Traveller origin, with developmental and epileptic encephalopathy-111 (DEE111; 620504), Ververi et al. (2023) identified a homozygous c.1010C-G transversion (c.1010C-G, NM_001242896.3) in the DEPDC5 gene, resulting in a thr337-to-arg (T337R) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families and was not present in the gnomAD database. Molecular modeling predicted that the mutation would result in a loss of protein stability and adversely affect protein function. Functional studies of the variant were not performed, but immunohistochemical studies of a skin sample from 1 of the patients was consistent with an overall increase in mTOR (601231) activity. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that the T337R mutation results in a partial loss of function.
In 3 patients from 2 unrelated consanguineous families (family 4 of Tunisian descent and family 5 of Lebanese descent), with developmental and epileptic encephalopathy-111 (DEE111; 620504), Ververi et al. (2023) identified a homozygous c.2416C-T transition (c.2416C-T, NM_001242896.3) in the DEPDC5 gene, resulting in an arg806-to-cys (R806C) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families and was not present in the gnomAD database. Molecular modeling predicted that the mutation would result in a loss of protein stability and adversely affect protein function. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that the R806C mutation results in a partial loss of function.
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