HGNC Approved Gene Symbol: KCTD7
Cytogenetic location: 7q11.21 Genomic coordinates (GRCh38) : 7:66,628,881-66,643,229 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.21 | Epilepsy, progressive myoclonic 3, with or without intracellular inclusions | 611726 | Autosomal recessive | 3 |
Members of the KCTD gene family, including KCTD7, encode predicted proteins containing an N-terminal domain that is homologous to the T1 domain in voltage-gated potassium channels (see KCNA1, 176260). KCTD7 displays a primary sequence and hydropathy profile indicating intracytoplasmic localization. EST database analysis showed that KCTD7 is expressed in human and mouse brain (Van Bogaert et al., 2007).
Staropoli et al. (2012) detected expression of a full-length 31-kD Kctd7 isoform in mouse brain. Other major immunoreactive bands included a 28-kD species in the spleen, liver, and kidneys, a 37-kD species in the kidneys, and a 62-kD form most likely corresponding to a stable dimer. The presence of multiple bands was consistent with alternative splicing and tissue-specific regulation.
Kousi et al. (2012) found expression of the Kctd7 gene in cultured mouse hippocampal cells. Expression was found in the cell soma, in neuritic varicosities along the developing neuronal extensions, and in neurite growth cones, but not in the nucleus. Kctd7 was widely expressed in neurons throughout the intact mouse brain, including in cortical neurons, in granular and pyramidal cell layers of the hippocampus, and in cerebellar Purkinje cells. However, not all neuronal cells were immunopositive for Kctd7, and expression was not seen in astrocytes or microglial cells. Expression was constant from P5 to 2 months in cerebellar lysates. Overexpression of KCTD7 in HeLa and COS-1 cells, which do not express endogenous KCTD7, showed diffuse cytosolic localization, with no colocalization with markers for endosomes, ER, Golgi, lysosomes, or the cytoskeleton.
The KCTD7 gene maps to chromosome 7q11.2 (Van Bogaert et al., 2007).
Azizieh et al. (2011) demonstrated that KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch-clamp experiments. Kctd7 was expressed in hippocampal and Purkinje cells of the murine brain. Immunoprecipitation assays showed that KCTD7 directly interacted with cullin-3 (CUL3; 603136), a component of the ubiquitin ligase complex.
In 3 affected members of a large consanguineous Moroccan family with progressive myoclonic epilepsy-3 (EPM3; 611726), Van Bogaert et al. (2007) identified a homozygous mutation in the KCTD7 gene (611725.0001).
In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy and pathologic findings of neuronal ceroid lipofuscinosis in multiple cell types, Staropoli et al. (2012) identified a homozygous mutation in the KCTD7 gene (R184C; 611725.0002). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Staropoli et al. (2012) designated the phenotype CLN14 (611726). KCTD7 mutations were not found in 32 additional CLN samples.
In affected members of 7 unrelated families with progressive myoclonic epilepsy-3, Kousi et al. (2012) identified 6 different mutations in the KCTD7 gene (see, e.g., 611725.0003-611725.0007). All mutations were in the homozygous or compound heterozygous state. The initial mutations were found in 2 probands by homozygosity mapping followed by candidate gene sequencing, and the other mutations were found by screening of the gene in 108 Turkish patients and 1 Pakistani patient with the phenotype. Four mutations were missense, 1 was an in-frame deletion, and 1 was truncating. None of the patients with KCTD7 mutations tested had evidence of neuronal ceroid lipofuscinosis on skin biopsy, and none of 22 additional patients with neuronal ceroid lipofuscinosis carried mutations in the KCTD7 gene.
In a 17-year-old Italian patient and a 7-year-old Pakistani patient with EPM3, Mastrangelo et al. (2019) identified homozygous missense mutations in the KCTD7 gene (A178V, 611725.0008 and G58R, 617725.0009, respectively). The mutations were identified by next-generation sequencing of a panel of 95 genes associated with early-onset epilepsies. The mutation segregated with the phenotype in both families.
In 3 affected members of a large consanguineous Moroccan family with progressive myoclonic epilepsy-3 (EPM3; 611726), Van Bogaert et al. (2007) identified a homozygous C-to-T transition in exon 2 of the KCTD7 gene, resulting in an arg99-to-ter (R99X) substitution. The patients had onset of myoclonic seizures and neurodegeneration between 16 and 24 months of age. The phenotype was severe and included mental retardation. The unaffected parents were heterozygous for the mutation. Ultrastructural analysis of a skin biopsy was normal.
In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy (EPM3; 611726) and intracellular inclusions, consistent with a diagnosis of neuronal ceroid lipofuscinosis (designated CLN14), Staropoli et al. (2012) identified a homozygous 550C-T transition in exon 4 of the KCTD7 gene, resulting in an arg184-to-cys (R184C) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for the mutation, which was not found in over 6,000 controls. In cerebellar cells, wildtype KCTD7 showed broad, punctate cytoplasmic localization and distinct signal at the plasma membrane, whereas mutant A184C showed more diffuse cytoplasmic localization, markedly diminished signaling at the plasma membrane, and prominent cytoplasmic aggregates. These results suggested that the mutation affects the trafficking and/or solubility of KCTD7. Studies in HEK293T cells showed that the R184C mutation abrogated the interaction with cullin-3 (CUL3; 603136), which Staropoli et al. (2012) suggested may lead to an accumulation of toxic intracellular proteins.
In a Turkish boy with progressive myoclonic epilepsy-3 (EPM3; 611726), Kousi et al. (2012) identified a homozygous 280C-T transition in exon 2 of the KCTD7 gene, resulting in an arg94-to-trp (R94W) substitution. The mutation was not found in 150 Turkish control chromosomes.
In 2 unrelated Turkish patients with progressive myoclonic epilepsy-3 (EPM3; 611726), Kousi et al. (2012) identified a homozygous 1-bp deletion (594delC) in exon 4 of the KCTD7 gene, resulting in a frameshift and premature termination (Ile199SerfsTer74).
In a Turkish boy with progressive myoclonic epilepsy-3 (EPM3; 611726), Kousi et al. (2012) identified a homozygous 818A-T transversion in exon 4 of the KCTD7 gene, resulting in an asn273-to-ile (N273I) substitution at a highly conserved residue. Another Turkish boy with the disorder was compound heterozygous for N273I and a 343G-T transversion, resulting in an asp115-to-tyr (D115Y; 611725.0006) substitution. The D115Y substitution did not occur at a highly conserved residue and was predicted to be benign, but neither mutation was found in 150 Turkish control chromosomes.
For discussion of the asp115-to-tyr (D115Y) mutation in the KCTD7 gene that was found in compound heterozygous state in a patient with progressive myoclonic epilepsy-3 (EPM3; 611726) by Kousi et al. (2012), see 611725.0005.
In 2 Pakistani sibs, born of consanguineous parents, with progressive myoclonic epilepsy-3 (EPM3; 611726), Kousi et al. (2012) identified a homozygous 322C-A transversion in exon 3 of the KCTD7 gene, resulting in a leu108-to-met (L108M) substitution at a highly conserved residue. The mutation was not found in 150 Turkish control chromosomes.
In a 17-year-old Italian patient with progressive myoclonic epilepsy-3 (EPM3; 611726), Mastrangelo et al. (2019) identified a homozygous c.533C-T transition (c.533C-T, NM_153033.4) in the KCTD7 gene, resulting in an ala178-to-val (A178V) substitution. The mutation was identified by next-generation sequencing of a panel of 95 genes associated with early-onset epilepsies. The variant was not present in the NCL or 1000 Genomes Project databases; it was present at a low frequency in the ExAC database (0.00002.47) and was not present in homozygous state in the gnomAD database. The mutation occurred at a conserved residue located outside of the BTB/POZ domain. Functional studies were not performed.
In a 7-year-old Pakistani girl with progressive myoclonic epilepsy-3 (EPM3; 611726), Mastrangelo et al. (2019) identified a homozygous c.172G-A transition (c.172G-A, NM_153033.4) in the KCTD7 gene, resulting in a gly58-to-arg (G58R) substitution in the KCTD7 gene. The mutation was identified by Sanger sequencing. The variant was absent in the 1000 Genomes Project database, and present at a low frequency in ExAC (8.241e-6) and gnomAD (4.065e-6). The mutation occurred at a conserved residue in the BTB/POZ domain. Functional studies were not performed. The patient had seizures, action myoclonus, and lysosomal storage material on a skin biopsy, consistent with neuronal ceroid lipofuscinosis.
Azizieh, R., Orduz, D., Van Bogaert, P., Bouschet, T., Rodriguez, W., Schiffmann, S. N., Pirson, I., Abramowicz, M. J. Progressive myoclonic epilepsy-associated gene KCTD7 is a regulator of potassium conductance in neurons. Molec. Neurobiol. 44: 111-121, 2011. [PubMed: 21710140] [Full Text: https://doi.org/10.1007/s12035-011-8194-0]
Kousi, M., Anttila, V., Schulz, A., Calafato, S., Jakkula, E., Riesch, E., Myllykangas, L., Kalimo, H., Topcu, M., Gokben, S., Alehan, F., Lemke, J. R., Alber, M., Palotie, A., Kopra, O., Lehesjoki, A.-E. Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene. J. Med. Genet. 49: 391-399, 2012. [PubMed: 22693283] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100859]
Mastrangelo, M., Sartori, S., Simonati, A., Brinciotti, M., Moro, F., Nosadini, M., Pezzini, F., Doccini, S., Santorelli, F. M., Leuzzi, V. Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: the multifaceted phenotypic spectrum of KCTD7-related disorders. Europ. J. Med. Genet. 62: 103591, 2019. Note: Electronic Article. [PubMed: 30500434] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.025]
Staropoli, J. F., Karaa, A, Lim, E. T., Kirby, A., Elbalalesy, N., Romansky, S. G., Leydiker, K. B., Coppel, S. H., Barone, R., Xin, W., Macdonald, M. E., Abdenur, J. E., Daly, M. J., Sims, K. B., Cotman, S. L. A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system. Am. J. Hum. Genet. 91: 202-208, 2012. [PubMed: 22748208] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.023]
Van Bogaert, P., Azizieh, R., Desir, J., Aeby, A., De Meirleir, L., Laes, J.-F., Christiaens, F., Abramowicz, M. J. Mutation of a potassium channel-related gene in progressive myoclonic epilepsy. Ann. Neurol. 61: 579-586, 2007. [PubMed: 17455289] [Full Text: https://doi.org/10.1002/ana.21121]