Alternative titles; symbols
HGNC Approved Gene Symbol: KPTN
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:47,475,150-47,485,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | Intellectual developmental disorder, autosomal recessive 41 | 615637 | Autosomal recessive | 3 |
KPTN binds to filamentous (F)-actin (see 102560) and localizes to the periphery of actin filaments, suggesting that it may be involved in actin dynamics (Bearer and Abraham, 1999).
Bearer (1992) reported that a monoclonal antibody (MAb-2E4) was raised against a human blood platelet protein, KPTN, which they called 2E4, that eluted from F-actin with ATP. Using MAb-2E4, they found that 2E4 localized to the microtubule-organizing center in undifferentiated rat PC12 cells. In NGF (162030)-differentiated PC12 cells, 2E4 relocalized along neurites and growth cones. Staining was granular, intense in the distal-most lamellae, and absent from cell bodies. In embryonic chicken fibroblasts, 2E4 localized to the periphery of actin filament-rich leading edges.
Using MAb-2E4 to screen a cDNA expression library grown from HEL cells expressing platelet proteins, Bearer and Abraham (1999) cloned human KPTN. The transcript contains 2 tandem ATG start sites, and the deduced 496-amino acid protein has a calculated molecular mass of 55 kD. Northern blot analysis detected an approximately 1.65-kb KPTN transcript in human cell lines. EST database analysis revealed KPTN expression in human infant and fetal brain, fetal liver/spleen, and fetal heart and in mouse mammary gland. Immunohistochemical analysis detected KPTN at the outermost edge of spreading human platelets. It also localized to the outermost third of actin filaments of subconfluent embryonic chicken fibroblasts, but not to stress fibers or adhesion plaques. Western blot analysis of activated human platelets detected KPTN at an apparent molecular mass of approximately 45 kD. KPTN was also detected in embryonic chicken fibroblasts, intestinal microvilli, and cochlea, but not in human red blood cells. Phase-contrast microscopy of embryonic chicken cochlea detected KPTN localized to the tips of stereocilia, with stronger staining of taller stereocilia in any single stereocilia staircase.
Using an in vitro actin-binding assay, Bearer (1992) found that 2E4 from embryonic chicken and PC12 cells bound 1 end of rabbit skeletal muscle F-actin elements.
Bearer and Abraham (1999) stated that KPTN binds the barbed end of F-actin. Using affinity chromatography, they confirmed that human KPTN bound F-actin and eluted with 5 mM ATP and 10 mM MgCl(2). KPTN was also extracted from chicken cochlear sensory epithelium with detergent and ATP.
In primary rat hippocampal cells, Baple et al. (2014) found that KPTN localized to neuronal growth cones during early development and later to postsynaptic F-actin-rich foci. KPTN localized to foci that also immunostained with SHANK2 (603290), a postsynaptic scaffolding protein. In COS-7 cells, KPTN localized to dynamic actin filaments in mobile fibroblasts. These findings suggested a role for KPTN in neuromorphogenesis.
MTOR complex-1 (mTORC1; see 601231) has a central role in regulating cell growth in response to diverse environmental signals. By coimmunoprecipitation analysis and coexpression in HEK293 cells, Wolfson et al. (2017) identified a protein complex containing KPTN, ITFG2 (617421), C12ORF66 (617420), and SZT2 (615463) that they designated KICSTOR (KPTN-, ITFG2-, C12ORF66-, and SZT2-containing regulator of mTORC1). The KICSTOR complex interacted with the GATOR1 and GATOR2 complexes, which regulate mTORC1 activation in response to nutrients. The SZT2 component of KICSTOR interacted with GATOR1, which in turn bound GATOR2. MTORC1 signaling was insensitive to amino acid or glucose starvation in cells lacking any of the KICSTOR components.
Using HEK293 cells, Gu et al. (2017) found that SAMTOR (BMT2; 617855) bound the GATOR1-KICSTOR 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.
Bearer et al. (2000) determined that the KPTN gene contains 11 exons and spans over 3.78 kb.
Using FISH, radiation hybrid analysis, and YAC screening Bearer et al. (2000) mapped the KPTN gene to chromosome 19q13.4.
In 4 affected individuals from 2 consanguineous Amish families with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637), Baple et al. (2014) identified a homozygous truncating mutation in the KPTN gene (S259X; 615620.0001). The mutation was found using a combination of homozygosity mapping and whole-exome sequencing. Five affected individuals from 2 additional consanguineous Amish families were compound heterozygous for S259X and an in-frame duplication in the KPTN gene (615620.0002). All 4 families were determined to be distantly related, consistent with 2 founder mutations in this community. Transfection of the mutations into COS-7 cells showed that the mutant proteins did not localize like wildtype protein to F-actin-rich lamellipodia, but rather accumulated at irregular perinuclear sites, suggesting a loss of normal activity. The truncated protein showed a more pronounced tendency to form such accumulations compared to the duplication mutation. Baple et al. (2014) suggested that the mutations resulted in a loss of KPTN function, which could lead to impairment of the neuronal actin cytoskeleton that is required for dendritic arborization or spine formation during neurogenesis.
In 2 Estonian sibs with MRT41, Pajusalu et al. (2015) identified a homozygous 1-bp duplication (c.665dupA; 615620.0003) in the KPTN gene, predicted to result in a frameshift (Gln222fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The findings indicated that the disorder is not restricted to the Amish population.
In a 9-year-old Caucasian boy with MRT41, Thiffault et al. (2020) identified compound heterozygous mutations in the KPTN gene, a previously identified in-frame duplication (615620.0002) and a splice site mutation (615620.0004). The mutations were found by whole-genome sequencing and confirmed by Sanger sequencing. The splice site mutation but not the duplication was inherited from the mother, suggesting that the variants were in trans.
In 2 Spanish sisters with MRT41, Pacio Miguez et al. (2020) identified a homozygous 2-bp duplication in the KPTN gene (615620.0005). No information regarding segregation was provided.
In 4 patients from 2 consanguineous Amish families with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637), Baple et al. (2014) identified a homozygous c.776C-A transversion in exon 8 of the KPTN gene, resulting in a ser259-to-ter (S259X) substitution. The mutation was found using a combination of homozygosity mapping and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the families. Seven heterozygous carriers were identified in 560 examined control chromosomes, yielding an allele frequency of approximately 0.012 in this community. The variant was also listed in the Exome Variant Server database (1 in 8,285 European American chromosomes). Subsequent screening of this gene among other Amish families with a similar disorder identified 2 more families who carried the S259X mutation in compound heterozygosity with an 18-bp in-frame duplication (c.714_731dup; 615620.0002) in exon 8, resulting in the protein change Met241_Gln246dup. The duplication was not listed in genomic sequence databases and was found in 1 of 560 Amish control chromosomes. The 4 nuclear families were determined to be distantly related, suggesting that these 2 founder mutations were trapped in this population. Transfection of the mutations into COS-7 cells showed that the mutant proteins did not localize like wildtype protein to F-actin-rich lamellipodia, but instead accumulated at irregular perinuclear sites, suggesting a loss of normal activity. The truncated protein showed a more pronounced tendency to form such accumulations compared to the duplication mutation. Baple et al. (2014) suggested that the mutations resulted in a loss of KPTN function, which could lead to impairment of the neuronal actin cytoskeleton that is required for dendritic arborization or spine formation during neurogenesis.
For discussion of the 18-bp in-frame duplication in exon 8 of the KPTN gene (c.714_731dup) that was found in compound heterozygous state in patients with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637) by Baple et al. (2014), see 615620.0001.
In a 9-year-old boy with MRT41, Thiffault et al. (2020) identified compound heterozygous mutations in the KPTN gene, c.714_731dup (c.714_731dup, NM_007059.2) and a c.394+1G-A transition (615620.0004) in intron 3, predicted to result in a splicing abnormality. The mutations were identified by whole-genome sequencing and confirmed by Sanger sequencing. The mother was shown to be a carrier of the splice site variant but not the duplication, indicating that the variants were in trans. The c.714_731dup variant was present in the gnomAD database at an allele frequency of 0.05%, and the c.394+1G-A variant was present in the gnomAD database at an allele frequency of 0.007%. Functional studies were not performed.
In 2 Estonian sibs with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637), Pajusalu et al. (2015) identified a homozygous 1-bp duplication (c.665dupA, NM_007059) in exon 7 of the KPTN gene, predicted to result in a frameshift (Gln222fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
For discussion of the c.394+1G-A transition (c.394+1G-A, NM_007059.2) in intron 3 of the KPTN gene, predicted to result in a splicing abnormality, that was identified in compound heterozygous state in a patient with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637) by Thiffault et al. (2020), see 615620.0002.
In 2 Spanish sibs with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637), Pacio Miguez et al. (2020) identified homozygosity for a 2-bp duplication (c.597_598dup, NM_007059.3) in the KPTN gene, resulting in a frameshift and premature termination (Ser200IlefsTer55). The variant was present in the gnomAD database at an allele frequency of 0.000103. No segregation information was provided, and no functional studies were performed.
Baple, E. L., Maroofian, R., Chioza, B. A., Izadi, M., Cross, H. E., Al-Turki, S., Barwick, K., Skrzypiec, A., Pawlak, R., Wagner, K., Coblentz, R., Zainy, T., Patton, M. A., Mansour, S., Rich, P., Qualmann, B., Hurles, M. E., Kessels, M. M., Crosby, A. H. Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am. J. Hum. Genet. 94: 87-94, 2014. [PubMed: 24239382] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.001]
Bearer, E. L., Abraham, M. T. 2E4 (Kaptin): a novel actin-associated protein from human blood platelets found in lamellipodia and the tips of the stereocilia of the inner ear. Europ. J. Cell Biol. 78: 117-126, 1999. [PubMed: 10099934] [Full Text: https://doi.org/10.1016/S0171-9335(99)80013-2]
Bearer, E. L., Chen, A. F., Chen, A. H., Li, Z., Mark, H.-F., Smith, R. J. H., Jackson, C. L. 2E4/Kaptin (KPTN)--a candidate gene for hearing loss locus, DFNA4. Ann. Hum. Genet. 64: 189-196, 2000. [PubMed: 11409409] [Full Text: https://doi.org/10.1046/j.1469-1809.2000.6430189.x]
Bearer, E. L. An actin-associated protein present in the microtubule organizing center and the growth cones of PC-12 cells. J. Neurosci. 12: 750-761, 1992. [PubMed: 1372044] [Full Text: https://doi.org/10.1523/JNEUROSCI.12-03-00750.1992]
Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., Sabatini, D. M. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358: 813-818, 2017. [PubMed: 29123071] [Full Text: https://doi.org/10.1126/science.aao3265]
Pacio Miguez, M., Santos-Simarro, F., Garcia-Minaur, S., Velazquez Fragua, R., Del Pozo, A., Solis, M., Jimenez Rodriguez, C., Rufo-Rabadan, V., Fernandez, V. E., Rueda, I., Gomez Del Pozo, M. V., Gallego, N., Lapunzina, P., Palomares-Bralo, M. Pathogenic variants in KPTN, a rare cause of macrocephaly and intellectual disability. (Letter) Am. J. Med. Genet. 182A: 2222-2225, 2020. [PubMed: 32808430] [Full Text: https://doi.org/10.1002/ajmg.a.61778]
Pajusalu, S., Reimand, T., Ounap, K. Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. Am. J. Med. Genet. 167A: 1913-1915, 2015. [PubMed: 25847626] [Full Text: https://doi.org/10.1002/ajmg.a.37105]
Thiffault, I., Atherton, A., Heese, B. A., T Abdelmoity, A., Pawar, K., Farrow, E., Zellmer, L., Miller, N., Soden, S., Saunders, C. Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing. Cold Spring Harbor Molec. Case Stud. 6: a003970, 2020. [PubMed: 32358097] [Full Text: https://doi.org/10.1101/mcs.a003970]
Wolfson, R. L., Chantranupong, L., Wyant, G. A., Gu, X., Orozco, J. M., Shen, K., Condon, K. J., Petri, S., Kedir, J., Scaria, S. M., Abu-Remaileh, M., Frankel, W. N., Sabatini, D. M. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543: 438-442, 2017. [PubMed: 28199306] [Full Text: https://doi.org/10.1038/nature21423]