* 603722

ELONGATOR COMPLEX PROTEIN 1; ELP1


Alternative titles; symbols

INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE COMPLEX-ASSOCIATED PROTEIN; IKBKAP
IKK COMPLEX-ASSOCIATED PROTEIN; IKAP
ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 1; ELP1
ELP1, YEAST, HOMOLOG OF


HGNC Approved Gene Symbol: ELP1

Cytogenetic location: 9q31.3     Genomic coordinates (GRCh38): 9:108,867,517-108,934,124 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q31.3 {Medulloblastoma} 155255 AD, AR, SMu 3
Dysautonomia, familial 223900 AR 3

TEXT

Description

IKAP was initially described as a scaffold protein of the IKK complex involved in NF-kappa-B (see 164011) activation, but a role for IKAP in this pathway was later disproved. IKAP is a component of elongator, a highly conserved transcription elongation factor complex that has histone acetyltransferase activity, primarily directed toward histone H3. A substantial fraction of elongator is cytoplasmic, however, suggesting that the complex performs additional functions (Close et al., 2006).


Cloning and Expression

Cohen et al. (1998) isolated large, IL1-inducible IKK complexes containing NF-kappa-B-inducing kinase (NIK; 604655), IKK-alpha (600664), IKK-beta (603258), I-kappa-B-alpha (164008), NF-kappa-B/RelA (164014), and a 150-kD protein that they called IKAP for 'IKK complex-associated protein.' The IKAP open reading frame of 3,996 nucleotides is flanked by 303 bp and 501 bp of 5-prime and 3-prime untranslated sequence, respectively. A 4.8-kb mRNA was detected in most human tissues. IKAP shows 22% overall identity with the yeast protein IKI3, which may be involved in the yeast response to toxins. There appeared to be 5 WD-like repeats.

Coli et al. (2001) cloned Ikbkap cDNA from mouse spleen. The mouse cDNA shares 77% nucleotide identity with human IKBKAP. The deduced mouse protein contains 1,333 amino acids, and the human protein contains 1,332.


Gene Function

Cohen et al. (1998) found that IKAP could bind NIK and IKKs through separate domains and assemble them into an active kinase complex. Thus, IKAP is a scaffold protein and a regulator for 3 different kinases involved in proinflammatory signaling. IKAP sequence encompassing only the fifth WD-like motif was sufficient for binding of NIK.

Krappmann et al. (2000) found IKBKAP associated with a high molecular mass complex containing additional proteins of 100, 70, 45, and 39 kD in HeLa cells. However, they found no association of IKBKAP with the IKK complex. Overexpression of IKBKAP repressed expression of reporter plasmids driven by thymidine kinase (188300) and beta-actin (102630) promoters, in addition to the NF-kappa-B promoter.

By examining the elongator complex purified from HeLa cells, Hawkes et al. (2002) found that the complex existed in 2 forms, the holo-elongator, which had histone acetyltransferase activity directed against histones H3 (see 602810) and H4 (see 602822), and a 3-subunit core form, which did not have histone acetyltransferase activity despite containing the catalytic subunit ELP3 (612722). ELP2 (616054) and IKAP were also detected in the core elongator complex. ELP4 (606985), ELP5 (615019), and ELP6 (615020) were detected in the active holo-elongator complex. Hawkes et al. (2002) proposed that the elongator complex serves a role in RNA polymerase II (see 180660)-associated chromatin remodeling during transcriptional elongation.

Rahl et al. (2005) found that the yeast homolog of IKBKAP, Elp1, physically interacted with the yeast Rab guanine nucleotide exchange factor Sec2. The Sec2 interaction domain of Elp1 was necessary for both Elp1 function and for the polarized localization of Sec2. Rahl et al. (2005) proposed that familial dysautonomia (FD; 223900), which results from mutation in IKBKAP, may be a defect in polarized exocytosis in neurons.

Using RNA interference and DNA microarray analysis, Close et al. (2006) found that IKAP depletion in human cells affected expression of a number of genes, with correlated effects on histone H3 acetylation and transcriptional elongation. Several affected genes were implicated in cell motility, and cells with decreased IKAP levels displayed motility defects.

Creppe et al. (2009) found that Elp1 was highly expressed throughout the rostrocaudal axis of the mouse telencephalon during development. Silencing of Elp1 impaired radial migration, resulting in accumulation of cells in the ventricular and subventricular zones and a reduced percentage of projection neurons in the cortical plate compared with controls. The migration defect was temporary, and Elp1-depleted neurons eventually reached their terminal destination. Elp1 silencing affected the morphology, but not the survival, of projection neurons in the cortical plate, with impaired growth of dendrites and axons, but not the soma perimeter. Depletion of ELP1 in a human colorectal carcinoma cell line resulted in abnormally rounded cell shapes and major delays in cell spreading. Endogenous ELP1 interacted with ELP3 in all human cell lines examined. ELP1 and ELP3 associated with microtubules, and depletion of either ELP1 or ELP3 resulted in reduced acetylation of alpha-tubulin (see TUBA1A; 602529).

Using RNA interference, Close et al. (2012) found that depletion of any of the elongator complex components Elp1, Elp3, Elp5 (615019), or Elp6 (615020) in B16-F10 mouse melanoma cells reduced cell motility in a wound-healing assay and reduced the capacity of cells to form colonies in soft agar.


Gene Structure

Coli et al. (2001) determined that the mouse Ikbkap gene, like the human IKBKAP gene, contains 37 exons. The mouse Ikbkap gene spans about 51 kb, and the consensus donor splice site of intron 20, which is altered in a major mutation (603722.0001) leading to familial dysautonomia (FD; 223900), is conserved in the mouse.


Mapping

By sequence analysis, Slaugenhaupt et al. (2001) mapped the IKBKAP gene to chromosome 9q31.

By backcross analysis, Coli et al. (2001) mapped the mouse Ikbkap gene to a central region of chromosome 4 that shows homology of synteny to human chromosome 9.


Molecular Genetics

Familial Dysautonomia

Familial dysautonomia (FD; 223900), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Blumenfeld et al. (1993) mapped the familial dysautonomia locus to 9q31; by haplotype analysis, Blumenfeld et al. (1999) narrowed the location to a 471-kb interval. They had shown that the ethnic bias is due to a founder effect, with more than 99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of the familial dysautonomia, Slaugenhaupt et al. (2001) sequenced the candidate region and cloned and characterized the 5 genes located therein. IKBKAP was one of these genes and was found to harbor 2 mutations that can cause FD. The major haplotype mutation was located at the donor splice site of intron 20 (IVS20DS+6T-C; 603722.0001). This mutation results in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wildtype message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wildtype, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in 4 patients is an arg696-to-pro missense mutation (603722.0002) in exon 19, which is predicted to disrupt a potential phosphorylation site.

Simultaneously and independently, Anderson et al. (2001) found the splice site mutation as the predominant one in familial dysautonomia, and identified, in individuals bearing a minor FD haplotype, the missense mutation in exon 19 that disrupts a consensus serine/threonine kinase phosphorylation site.

Cuajungco et al. (2003) characterized the consequences of the major splice site mutation in IKBKAP responsible for FD (603722.0001) by examining the ratio of wildtype to mutant IKBKAP transcript in Epstein-Barr virus-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with the disorder. They consistently found that wildtype IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem dysautonomia tissues. Furthermore, a corresponding decrease in the level of wildtype protein was seen in FD cell lines and tissues. The wildtype-to-mutant ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative PCR, the authors found that relative wildtype-to-mutant IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggested that the relative inefficiency of wildtype IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD.

Medulloblastoma

Waszak et al. (2020) analyzed all protein-coding genes and identified and replicated rare germline loss-of-function variants across the ELP1 gene in 14% of pediatric patients with medulloblastoma in subgroup sonic hedgehog (MB-SHH; 155255). Parent-offspring and pedigree analysis identified germline mutations in 2 families with a history of pediatric medulloblastoma; see 603722.0004 and 603722.0005. ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among pediatric patients with MB-SHH. ELP1-associated medulloblastomas were restricted to the SHH-alpha subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1 (601309). Tumors from patients with ELP1-associated MB-SHH were characterized by a destabilized elongator complex, loss of elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to elongator deficiency in model systems.


Pathogenesis

Lee et al. (2009) reported the derivation of patient-specific FD induced pluripotent stem cells (iPSCs) and the directed differentiation into cells of all 3 germ layers including peripheral neurons. Gene expression analysis in purified FD iPSC-derived lineages demonstrated tissue-specific missplicing of IKBKAP in vitro. Patient-specific neural crest precursors expressed particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis was further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behavior. Furthermore, Lee et al. (2009) used FD iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Lee et al. (2009) concluded that their study illustrated the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.


Animal Model

Hims et al. (2007) created transgenic mice expressing human IKBKAP with the FD-associated IVS20DS+6T-C splice mutation (603722.0001). The mutant IKBKAP transgene was misspliced in transgenic mice in a tissue-specific manner that replicated the pattern seen in FD patient tissues. In both FD and transgenic mouse tissues, missplicing predominated in neuronal tissues compared with nonneuronal tissues, and the most accurate splicing was seen in heart and kidney.

Morini et al. (2016) generated a transgenic mouse model of FD with the exon 20 splice site mutation (TgFD9;Ikbkap(delta20/flox)). Mutant mice recapitulated many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments.

In transgenic male mice carrying the human exon 20 splice site mutation, Morini et al. (2019) found that treatment right after birth with oral kinetin, a small molecule splicing modulator, resulted in improved sensorimotor coordination, prevention of spinal deformities, and significantly increased survival of proprioceptive neurons in the peripheral nervous system. These clinical benefits were associated with the increased expression of normal IKBKAP transcripts, as well as increased protein expression. Treatment of human fibroblasts carrying the splice site mutation resulted in increased IKBKAP gene expression without significant changes in overall genomic splicing, suggesting that kinetin shows selective splicing modulation activity. The study provided a proof of concept that targeting the underlying genetic mechanism in FD can result in clinical benefits.

Romano et al. (2022) treated transgenic mice that were heterozygous for the human exon 20 splice site mutation with an AAV9 vector carrying a modified U1 snRNA targeting the exon 20 skipping. The mutant mice were treated with intraventricular and intraperitoneal injections of the modified U1 snRNA at postnatal days 0 and 2, respectively. Treatment resulted in increased wildtype Elp1 gene and protein expression and increased survival of the mutant mice. The treated mice exhibited improved motor and proprioceptive function and improved cardiac and renal function. Gene expression studies in dorsal root ganglia from the treated mice demonstrated very few off-target effects. Romano et al. (2022) concluded that the phenotypic improvements in the AAV-treated mutant mice, in conjunction with evidence for few off-target effects, provided promising evidence for the application of this therapy in patients.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 DYSAUTONOMIA, FAMILIAL

ELP1, IVS20DS, T-C, +6
  
RCV000006458...

Slaugenhaupt et al. (2001) found that more than 99.5% of disease alleles causing familial dysautonomia (223900) in Ashkenazi Jewish individuals carried a donor splice site mutation (IVS20+6T-C) which leads to deletion of exon 20 from mRNA. Haplotype analyses were consistent with a common founder. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia.

To determine why the mutation in position 6 of intron 20 causes aberrant splicing only in certain cases, Ibrahim et al. (2007) used an in silico approach to identify potential sequences involved in exon 20 skipping. Computational analyses of the exon 20 5-prime splice site itself predicted that this 9-nucleotide splicing signal, even when it contains the T-C mutation, is not sufficiently weak to explain the familial dysautonomia phenotype. However, the computational analysis predicted that both the upstream 3-prime splice site and exon 20 contain weak splicing signals, indicating that the familial dysautonomia 5-prime splice site, together with the surrounding splicing signals, are not adequate for defining exon 20. These in silico predictions were corroborated by IKBKAP minigenes in a rapid and simple in vitro coupled RNA polymerase II (see 180660) transcription/splicing assay. The weak splicing signals that flank the T-C mutation were validated as the underlying cause of familial dysautonomia in vivo using transient transfection assays. Together, the study demonstrated the general utility of combining in silico data with an in vitro RNA polymerase II transcription/splicing system for rapidly identifying critical sequences that underlie the numerous splicing disorders caused by otherwise silent mutations.


.0002 DYSAUTONOMIA, FAMILIAL

ELP1, ARG696PRO
  
RCV000006459...

In 4 Ashkenazi Jewish patients with familial dysautonomia (223900), Slaugenhaupt et al. (2001) identified an arg696-to-pro (R696P) mutation in exon 19 of the IKBKAP gene. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia.

Dong et al. (2002) developed a single PCR and allele-specific oligonucleotide (ASO) hybridization assay for detection of both the IVS20+6T-C splice site mutation (603722.0001) and the R696P mutation found in Ashkenazi Jews. Screening of 2,518 anonymous Ashkenazi Jewish individuals from the New York metropolitan area revealed a carrier frequency for the splice mutation of 1 in 32 (3.2%; 95% CI 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P deletion, indicating that the mutation is rare in this population (less than 1 in 2,500).


.0003 DYSAUTONOMIA, FAMILIAL

ELP1, PRO914LEU
  
RCV000006460...

In a patient with familial dysautonomia (223900), previously reported by Blumenfeld et al. (1999), Leyne et al. (2003) identified compound heterozygosity for the major FD haplotype (603722.0001), which was inherited from the Ashkenazi Jewish father, and a 3051C-T transition in exon 26 of the IKBKAP gene, resulting in a pro914-to-leu (P914L) substitution, from the mother, who was of Irish-German/Sicilian heritage. The patient fulfilled all diagnostic criteria for FD other than pure Ashkenazi Jewish ancestry.


.0004 MEDULLOBLASTOMA

ELP1, 1-BP DUP, 138T
  
RCV001730181...

In a father and daughter with medulloblastoma (155255), Waszak et al. (2020) identified a heterozygous germline 1-bp duplication (c.138dupT) in the ELP1 gene, resulting in a frameshift. The father was diagnosed at age 17 years and the daughter at age 4 years. There was a paternal family history of death due to brain tumor and the father's sister died of medulloblastoma.

Hamosh (2020) noted that the c.138dupT variant was not present in the gnomAD database.


.0005 MEDULLOBLASTOMA

ELP1, c.312T-C
  
RCV001730182

In a 23-year-old man who was diagnosed at age 19 years with medulloblastoma (155255), Waszak et al. (2020) identified a heterozygous germline c.312T-C transition in the ELP1 gene. His mother, who was in her fifties, carried the mutation but had not developed medulloblastoma. A distant maternal relative who was diagnosed with medulloblastoma at age 4 years had not been tested for the mutation.

Hamosh (2020) noted that the c.312T-C variant was not present in the gnomAD database.


REFERENCES

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  2. Blumenfeld, A., Slaugenhaupt, S. A., Axelrod, F. B., Lucente, D. E., Maayan, C., Liebert, C. B., Ozelius, L. J., Trofatter, J. A., Haines, J. L., Breakefield, X. O., Gusella, J. F. Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis. Nature Genet. 4: 160-164, 1993. [PubMed: 8102296, related citations] [Full Text]

  3. Blumenfeld, A., Slaugenhaupt, S. A., Liebert, C. B., Temper, V., Maayan, C., Gill, S., Lucente, D. E., Idelson, M., MacCormack, K., Monahan, M. A., Mull, J., Leyne, M., Mendillo, M., Schiripo, T., Mishori, E., Breakefield, X., Axelrod, F. B., Gusella, J. F. Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31. Am. J. Hum. Genet. 64: 1110-1118, 1999. [PubMed: 10090896, related citations] [Full Text]

  4. Close, P., Gillard, M., Ladang, A., Jiang, Z., Papuga, J., Hawkes, N., Nguyen, L., Chapelle, J.-P., Bouillenne, F., Svejstrup, J., Fillet, M., Chariot, A. DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of elongator. J. Biol. Chem. 287: 32535-32545, 2012. [PubMed: 22854966, images, related citations] [Full Text]

  5. Close, P., Hawkes, N., Cornez, I., Creppe, C., Lambert, C. A., Rogister, B., Siebenlist, U., Merville, M.-P., Slaugenhaupt, S. A., Bours, V., Svejstrup, J. Q., Chariot, A. Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Molec. Cell 22: 521-531, 2006. [PubMed: 16713582, related citations] [Full Text]

  6. Cohen, L., Henzel, W. J., Baeuerle, P. A. IKAP is a scaffold protein of the I-kappa-B kinase complex. Nature 395: 292-296, 1998. [PubMed: 9751059, related citations] [Full Text]

  7. Coli, R., Anderson, S. L., Volpi, S. A., Rubin, B. Y. Genomic organization and chromosomal localization of the mouse IKBKAP gene. Gene 279: 81-89, 2001. [PubMed: 11722848, related citations] [Full Text]

  8. Creppe, C., Malinouskaya, L., Volvert, M.-L., Gillard, M., Close, P., Malaise, O., Laguesse, S., Cornez, I., Rahmouni, S., Ormenese, S., Belachew, S., Malgrange, B., Chapelle, J.-P., Siebenlist, U., Moonen, G., Chariot, A., Nguyen, L. Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. Cell 136: 551-564, 2009. [PubMed: 19185337, related citations] [Full Text]

  9. Cuajungco, M. P., Leyne, M., Mull, J., Gill, S. P., Lu, W., Zagzag, D., Axelrod, F. B., Maayan, C., Gusella, J. F., Slaugenhaupt, S. A. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am. J. Hum. Genet. 72: 749-758, 2003. [PubMed: 12577200, images, related citations] [Full Text]

  10. Dong, J., Edelmann, L., Bajwa, A. M., Kornreich, R., Desnick, R. J. Familial dysautonomia: detection of the IKBKAP IVS20+6T-C and R696P mutations and frequencies among Ashkenazi Jews. Am. J. Med. Genet. 110: 253-257, 2002. [PubMed: 12116234, related citations] [Full Text]

  11. Hamosh, A. Personal Communication. Baltimore, Md. 6/7/2020.

  12. Hawkes, N. A., Otero, G., Winkler, G. S., Marshall, N., Dahmus, M. E., Krappmann, D., Scheidereit, C., Thomas, C. L., Schiavo, G., Erdjument-Bromage, H., Tempst, P., Svejstrup, J. Q. Purification and characterization of the human elongator complex. J. Biol. Chem. 277: 3047-3052, 2002. [PubMed: 11714725, related citations] [Full Text]

  13. Hims, M. M., Shetty, R. S., Pickel, J., Mull, J., Leyne, M., Liu, L., Gusella, J. F., Slaugenhaupt, S. A. A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect. Genomics 90: 389-396, 2007. [PubMed: 17644305, images, related citations] [Full Text]

  14. Ibrahim, E. C., Hims, M. M., Shomron, N., Burge, C. B., Slaugenhaupt, S. A., Reed, R. Weak definition of IKBKAP exon 20 leads to aberrant splicing in familial dysautonomia. Hum. Mutat. 28: 41-53, 2007. [PubMed: 16964593, related citations] [Full Text]

  15. Krappmann, D., Hatada, E. N., Tegethoff, S., Li, J., Klippel, A., Giese, K., Baeuerle, P. A., Scheidereit, C. The I-kappa-B kinase (IKK) complex is tripartite and contains IKK-gamma but not IKAP as a regular component. J. Biol. Chem. 275: 29779-29787, 2000. [PubMed: 10893415, related citations] [Full Text]

  16. Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461: 402-406, 2009. [PubMed: 19693009, images, related citations] [Full Text]

  17. Leyne, M., Mull, J., Gill, S. P., Cuajungco, M. P., Oddoux, C., Blumenfeld, A., Maayan, C., Guesella, J. F., Axelrod, F. B., Slaugenhaupt, S. A. Identification of the first non-Jewish mutation in familial dysautonomia. Am. J. Med. Genet. 118A: 305-308, 2003. [PubMed: 12687659, related citations] [Full Text]

  18. Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I. Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia. Hum. Molec. Genet. 25: 1116-1128, 2016. [PubMed: 26769677, images, related citations] [Full Text]

  19. Morini, E., Gao, D., Montgomery, C. M., Salani, M., Mazzasette, C., Krussig, T. A., Swain, B., Dietrich, P., Narasimhan, J., Gabbeta, V., Dakka, A., Hedrick, J., Zhao, X., Weetall, M., Naryshkin, N. A., Wojtkiewicz, G. G., Ko, C.-P., Talkowski, M. E., Dragatsis, I., Slaugenhaupt, S. A. ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia. Am. J. Hum. Genet. 104: 638-650, 2019. [PubMed: 30905397, images, related citations] [Full Text]

  20. Rahl, P. B., Chen, C. Z., Collins, R. N. Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation. Molec. Cell 17: 841-853, 2005. [PubMed: 15780940, related citations] [Full Text]

  21. Romano, G., Riccardi, F., Bussani, E., Vodret, S., Licastro, D., Ragone, I., Ronzitti, G., Morini, E., Slaugenhaupt, S. A., Pagani, F. Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA. Am. J. Hum. Genet. 109: 1534-1548, 2022. [PubMed: 35905737, related citations] [Full Text]

  22. Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68: 598-605, 2001. [PubMed: 11179008, images, related citations] [Full Text]

  23. Waszak, S. M., Robinson, G. W., Gudenas, B. L., Smith, K. S., Forget, A., Kojic, M., Garcia-Lopez, J., Hadley, J., Hamilton, K. V., Indersie, E., Buchhalter, I., Kerssemakers, J., and 51 others. Germline Elongator mutations in sonic hedgehog medulloblastoma. Nature 580: 396-401, 2020. [PubMed: 32296180, images, related citations] [Full Text]


Hilary J. Vernon - updated : 10/03/2022
Ada Hamosh - updated : 10/13/2021
Cassandra L. Kniffin - updated : 02/10/2020
Patricia A. Hartz - updated : 10/14/2014
Patricia A. Hartz - updated : 1/11/2013
Ada Hamosh - updated : 10/19/2009
Patricia A. Hartz - updated : 4/8/2009
Patricia A. Hartz - updated : 9/21/2007
Victor A. McKusick - updated : 3/12/2007
Patricia A. Hartz - updated : 7/18/2006
Patricia A. Hartz - updated : 4/19/2005
Deborah L. Stone - updated : 11/15/2004
Victor A. McKusick - updated : 2/28/2003
Victor A. McKusick - updated : 7/2/2002
Victor A. McKusick - updated : 3/19/2001
Creation Date:
Ada Hamosh : 4/12/1999
carol : 10/04/2022
carol : 10/03/2022
carol : 10/14/2021
carol : 10/13/2021
alopez : 01/28/2021
alopez : 11/20/2020
carol : 02/12/2020
alopez : 02/11/2020
ckniffin : 02/10/2020
mgross : 10/14/2014
mcolton : 10/14/2014
mgross : 1/15/2013
terry : 1/11/2013
carol : 6/23/2011
alopez : 10/26/2009
terry : 10/19/2009
wwang : 8/14/2009
mgross : 4/8/2009
mgross : 4/8/2009
mgross : 9/26/2007
terry : 9/21/2007
alopez : 3/21/2007
terry : 3/12/2007
wwang : 12/5/2006
terry : 12/4/2006
mgross : 7/19/2006
terry : 7/18/2006
mgross : 4/20/2005
terry : 4/19/2005
carol : 12/22/2004
tkritzer : 11/15/2004
carol : 8/4/2004
tkritzer : 3/7/2003
tkritzer : 3/6/2003
terry : 2/28/2003
cwells : 7/15/2002
terry : 7/2/2002
cwells : 3/30/2001
cwells : 3/29/2001
terry : 3/19/2001
carol : 3/15/2000
alopez : 4/12/1999

* 603722

ELONGATOR COMPLEX PROTEIN 1; ELP1


Alternative titles; symbols

INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE COMPLEX-ASSOCIATED PROTEIN; IKBKAP
IKK COMPLEX-ASSOCIATED PROTEIN; IKAP
ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 1; ELP1
ELP1, YEAST, HOMOLOG OF


HGNC Approved Gene Symbol: ELP1

SNOMEDCT: 1156923005, 29159009, 443333004;   ICD10CM: G90.1;  


Cytogenetic location: 9q31.3     Genomic coordinates (GRCh38): 9:108,867,517-108,934,124 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q31.3 {Medulloblastoma} 155255 Autosomal dominant; Autosomal recessive; Somatic mutation 3
Dysautonomia, familial 223900 Autosomal recessive 3

TEXT

Description

IKAP was initially described as a scaffold protein of the IKK complex involved in NF-kappa-B (see 164011) activation, but a role for IKAP in this pathway was later disproved. IKAP is a component of elongator, a highly conserved transcription elongation factor complex that has histone acetyltransferase activity, primarily directed toward histone H3. A substantial fraction of elongator is cytoplasmic, however, suggesting that the complex performs additional functions (Close et al., 2006).


Cloning and Expression

Cohen et al. (1998) isolated large, IL1-inducible IKK complexes containing NF-kappa-B-inducing kinase (NIK; 604655), IKK-alpha (600664), IKK-beta (603258), I-kappa-B-alpha (164008), NF-kappa-B/RelA (164014), and a 150-kD protein that they called IKAP for 'IKK complex-associated protein.' The IKAP open reading frame of 3,996 nucleotides is flanked by 303 bp and 501 bp of 5-prime and 3-prime untranslated sequence, respectively. A 4.8-kb mRNA was detected in most human tissues. IKAP shows 22% overall identity with the yeast protein IKI3, which may be involved in the yeast response to toxins. There appeared to be 5 WD-like repeats.

Coli et al. (2001) cloned Ikbkap cDNA from mouse spleen. The mouse cDNA shares 77% nucleotide identity with human IKBKAP. The deduced mouse protein contains 1,333 amino acids, and the human protein contains 1,332.


Gene Function

Cohen et al. (1998) found that IKAP could bind NIK and IKKs through separate domains and assemble them into an active kinase complex. Thus, IKAP is a scaffold protein and a regulator for 3 different kinases involved in proinflammatory signaling. IKAP sequence encompassing only the fifth WD-like motif was sufficient for binding of NIK.

Krappmann et al. (2000) found IKBKAP associated with a high molecular mass complex containing additional proteins of 100, 70, 45, and 39 kD in HeLa cells. However, they found no association of IKBKAP with the IKK complex. Overexpression of IKBKAP repressed expression of reporter plasmids driven by thymidine kinase (188300) and beta-actin (102630) promoters, in addition to the NF-kappa-B promoter.

By examining the elongator complex purified from HeLa cells, Hawkes et al. (2002) found that the complex existed in 2 forms, the holo-elongator, which had histone acetyltransferase activity directed against histones H3 (see 602810) and H4 (see 602822), and a 3-subunit core form, which did not have histone acetyltransferase activity despite containing the catalytic subunit ELP3 (612722). ELP2 (616054) and IKAP were also detected in the core elongator complex. ELP4 (606985), ELP5 (615019), and ELP6 (615020) were detected in the active holo-elongator complex. Hawkes et al. (2002) proposed that the elongator complex serves a role in RNA polymerase II (see 180660)-associated chromatin remodeling during transcriptional elongation.

Rahl et al. (2005) found that the yeast homolog of IKBKAP, Elp1, physically interacted with the yeast Rab guanine nucleotide exchange factor Sec2. The Sec2 interaction domain of Elp1 was necessary for both Elp1 function and for the polarized localization of Sec2. Rahl et al. (2005) proposed that familial dysautonomia (FD; 223900), which results from mutation in IKBKAP, may be a defect in polarized exocytosis in neurons.

Using RNA interference and DNA microarray analysis, Close et al. (2006) found that IKAP depletion in human cells affected expression of a number of genes, with correlated effects on histone H3 acetylation and transcriptional elongation. Several affected genes were implicated in cell motility, and cells with decreased IKAP levels displayed motility defects.

Creppe et al. (2009) found that Elp1 was highly expressed throughout the rostrocaudal axis of the mouse telencephalon during development. Silencing of Elp1 impaired radial migration, resulting in accumulation of cells in the ventricular and subventricular zones and a reduced percentage of projection neurons in the cortical plate compared with controls. The migration defect was temporary, and Elp1-depleted neurons eventually reached their terminal destination. Elp1 silencing affected the morphology, but not the survival, of projection neurons in the cortical plate, with impaired growth of dendrites and axons, but not the soma perimeter. Depletion of ELP1 in a human colorectal carcinoma cell line resulted in abnormally rounded cell shapes and major delays in cell spreading. Endogenous ELP1 interacted with ELP3 in all human cell lines examined. ELP1 and ELP3 associated with microtubules, and depletion of either ELP1 or ELP3 resulted in reduced acetylation of alpha-tubulin (see TUBA1A; 602529).

Using RNA interference, Close et al. (2012) found that depletion of any of the elongator complex components Elp1, Elp3, Elp5 (615019), or Elp6 (615020) in B16-F10 mouse melanoma cells reduced cell motility in a wound-healing assay and reduced the capacity of cells to form colonies in soft agar.


Gene Structure

Coli et al. (2001) determined that the mouse Ikbkap gene, like the human IKBKAP gene, contains 37 exons. The mouse Ikbkap gene spans about 51 kb, and the consensus donor splice site of intron 20, which is altered in a major mutation (603722.0001) leading to familial dysautonomia (FD; 223900), is conserved in the mouse.


Mapping

By sequence analysis, Slaugenhaupt et al. (2001) mapped the IKBKAP gene to chromosome 9q31.

By backcross analysis, Coli et al. (2001) mapped the mouse Ikbkap gene to a central region of chromosome 4 that shows homology of synteny to human chromosome 9.


Molecular Genetics

Familial Dysautonomia

Familial dysautonomia (FD; 223900), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Blumenfeld et al. (1993) mapped the familial dysautonomia locus to 9q31; by haplotype analysis, Blumenfeld et al. (1999) narrowed the location to a 471-kb interval. They had shown that the ethnic bias is due to a founder effect, with more than 99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of the familial dysautonomia, Slaugenhaupt et al. (2001) sequenced the candidate region and cloned and characterized the 5 genes located therein. IKBKAP was one of these genes and was found to harbor 2 mutations that can cause FD. The major haplotype mutation was located at the donor splice site of intron 20 (IVS20DS+6T-C; 603722.0001). This mutation results in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wildtype message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wildtype, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in 4 patients is an arg696-to-pro missense mutation (603722.0002) in exon 19, which is predicted to disrupt a potential phosphorylation site.

Simultaneously and independently, Anderson et al. (2001) found the splice site mutation as the predominant one in familial dysautonomia, and identified, in individuals bearing a minor FD haplotype, the missense mutation in exon 19 that disrupts a consensus serine/threonine kinase phosphorylation site.

Cuajungco et al. (2003) characterized the consequences of the major splice site mutation in IKBKAP responsible for FD (603722.0001) by examining the ratio of wildtype to mutant IKBKAP transcript in Epstein-Barr virus-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with the disorder. They consistently found that wildtype IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem dysautonomia tissues. Furthermore, a corresponding decrease in the level of wildtype protein was seen in FD cell lines and tissues. The wildtype-to-mutant ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative PCR, the authors found that relative wildtype-to-mutant IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggested that the relative inefficiency of wildtype IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD.

Medulloblastoma

Waszak et al. (2020) analyzed all protein-coding genes and identified and replicated rare germline loss-of-function variants across the ELP1 gene in 14% of pediatric patients with medulloblastoma in subgroup sonic hedgehog (MB-SHH; 155255). Parent-offspring and pedigree analysis identified germline mutations in 2 families with a history of pediatric medulloblastoma; see 603722.0004 and 603722.0005. ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among pediatric patients with MB-SHH. ELP1-associated medulloblastomas were restricted to the SHH-alpha subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1 (601309). Tumors from patients with ELP1-associated MB-SHH were characterized by a destabilized elongator complex, loss of elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to elongator deficiency in model systems.


Pathogenesis

Lee et al. (2009) reported the derivation of patient-specific FD induced pluripotent stem cells (iPSCs) and the directed differentiation into cells of all 3 germ layers including peripheral neurons. Gene expression analysis in purified FD iPSC-derived lineages demonstrated tissue-specific missplicing of IKBKAP in vitro. Patient-specific neural crest precursors expressed particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis was further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behavior. Furthermore, Lee et al. (2009) used FD iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Lee et al. (2009) concluded that their study illustrated the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.


Animal Model

Hims et al. (2007) created transgenic mice expressing human IKBKAP with the FD-associated IVS20DS+6T-C splice mutation (603722.0001). The mutant IKBKAP transgene was misspliced in transgenic mice in a tissue-specific manner that replicated the pattern seen in FD patient tissues. In both FD and transgenic mouse tissues, missplicing predominated in neuronal tissues compared with nonneuronal tissues, and the most accurate splicing was seen in heart and kidney.

Morini et al. (2016) generated a transgenic mouse model of FD with the exon 20 splice site mutation (TgFD9;Ikbkap(delta20/flox)). Mutant mice recapitulated many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments.

In transgenic male mice carrying the human exon 20 splice site mutation, Morini et al. (2019) found that treatment right after birth with oral kinetin, a small molecule splicing modulator, resulted in improved sensorimotor coordination, prevention of spinal deformities, and significantly increased survival of proprioceptive neurons in the peripheral nervous system. These clinical benefits were associated with the increased expression of normal IKBKAP transcripts, as well as increased protein expression. Treatment of human fibroblasts carrying the splice site mutation resulted in increased IKBKAP gene expression without significant changes in overall genomic splicing, suggesting that kinetin shows selective splicing modulation activity. The study provided a proof of concept that targeting the underlying genetic mechanism in FD can result in clinical benefits.

Romano et al. (2022) treated transgenic mice that were heterozygous for the human exon 20 splice site mutation with an AAV9 vector carrying a modified U1 snRNA targeting the exon 20 skipping. The mutant mice were treated with intraventricular and intraperitoneal injections of the modified U1 snRNA at postnatal days 0 and 2, respectively. Treatment resulted in increased wildtype Elp1 gene and protein expression and increased survival of the mutant mice. The treated mice exhibited improved motor and proprioceptive function and improved cardiac and renal function. Gene expression studies in dorsal root ganglia from the treated mice demonstrated very few off-target effects. Romano et al. (2022) concluded that the phenotypic improvements in the AAV-treated mutant mice, in conjunction with evidence for few off-target effects, provided promising evidence for the application of this therapy in patients.


ALLELIC VARIANTS 5 Selected Examples):

.0001   DYSAUTONOMIA, FAMILIAL

ELP1, IVS20DS, T-C, +6
SNP: rs111033171, gnomAD: rs111033171, ClinVar: RCV000006458, RCV000058928, RCV000789357, RCV002460887, RCV003444194

Slaugenhaupt et al. (2001) found that more than 99.5% of disease alleles causing familial dysautonomia (223900) in Ashkenazi Jewish individuals carried a donor splice site mutation (IVS20+6T-C) which leads to deletion of exon 20 from mRNA. Haplotype analyses were consistent with a common founder. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia.

To determine why the mutation in position 6 of intron 20 causes aberrant splicing only in certain cases, Ibrahim et al. (2007) used an in silico approach to identify potential sequences involved in exon 20 skipping. Computational analyses of the exon 20 5-prime splice site itself predicted that this 9-nucleotide splicing signal, even when it contains the T-C mutation, is not sufficiently weak to explain the familial dysautonomia phenotype. However, the computational analysis predicted that both the upstream 3-prime splice site and exon 20 contain weak splicing signals, indicating that the familial dysautonomia 5-prime splice site, together with the surrounding splicing signals, are not adequate for defining exon 20. These in silico predictions were corroborated by IKBKAP minigenes in a rapid and simple in vitro coupled RNA polymerase II (see 180660) transcription/splicing assay. The weak splicing signals that flank the T-C mutation were validated as the underlying cause of familial dysautonomia in vivo using transient transfection assays. Together, the study demonstrated the general utility of combining in silico data with an in vitro RNA polymerase II transcription/splicing system for rapidly identifying critical sequences that underlie the numerous splicing disorders caused by otherwise silent mutations.


.0002   DYSAUTONOMIA, FAMILIAL

ELP1, ARG696PRO
SNP: rs137853022, gnomAD: rs137853022, ClinVar: RCV000006459, RCV000789660, RCV001380395, RCV002482833

In 4 Ashkenazi Jewish patients with familial dysautonomia (223900), Slaugenhaupt et al. (2001) identified an arg696-to-pro (R696P) mutation in exon 19 of the IKBKAP gene. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia.

Dong et al. (2002) developed a single PCR and allele-specific oligonucleotide (ASO) hybridization assay for detection of both the IVS20+6T-C splice site mutation (603722.0001) and the R696P mutation found in Ashkenazi Jews. Screening of 2,518 anonymous Ashkenazi Jewish individuals from the New York metropolitan area revealed a carrier frequency for the splice mutation of 1 in 32 (3.2%; 95% CI 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P deletion, indicating that the mutation is rare in this population (less than 1 in 2,500).


.0003   DYSAUTONOMIA, FAMILIAL

ELP1, PRO914LEU
SNP: rs28939712, ClinVar: RCV000006460, RCV000789661

In a patient with familial dysautonomia (223900), previously reported by Blumenfeld et al. (1999), Leyne et al. (2003) identified compound heterozygosity for the major FD haplotype (603722.0001), which was inherited from the Ashkenazi Jewish father, and a 3051C-T transition in exon 26 of the IKBKAP gene, resulting in a pro914-to-leu (P914L) substitution, from the mother, who was of Irish-German/Sicilian heritage. The patient fulfilled all diagnostic criteria for FD other than pure Ashkenazi Jewish ancestry.


.0004   MEDULLOBLASTOMA

ELP1, 1-BP DUP, 138T
SNP: rs1564110292, ClinVar: RCV001730181, RCV002246468

In a father and daughter with medulloblastoma (155255), Waszak et al. (2020) identified a heterozygous germline 1-bp duplication (c.138dupT) in the ELP1 gene, resulting in a frameshift. The father was diagnosed at age 17 years and the daughter at age 4 years. There was a paternal family history of death due to brain tumor and the father's sister died of medulloblastoma.

Hamosh (2020) noted that the c.138dupT variant was not present in the gnomAD database.


.0005   MEDULLOBLASTOMA

ELP1, c.312T-C
SNP: rs1291760879, gnomAD: rs1291760879, ClinVar: RCV001730182

In a 23-year-old man who was diagnosed at age 19 years with medulloblastoma (155255), Waszak et al. (2020) identified a heterozygous germline c.312T-C transition in the ELP1 gene. His mother, who was in her fifties, carried the mutation but had not developed medulloblastoma. A distant maternal relative who was diagnosed with medulloblastoma at age 4 years had not been tested for the mutation.

Hamosh (2020) noted that the c.312T-C variant was not present in the gnomAD database.


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Contributors:
Hilary J. Vernon - updated : 10/03/2022
Ada Hamosh - updated : 10/13/2021
Cassandra L. Kniffin - updated : 02/10/2020
Patricia A. Hartz - updated : 10/14/2014
Patricia A. Hartz - updated : 1/11/2013
Ada Hamosh - updated : 10/19/2009
Patricia A. Hartz - updated : 4/8/2009
Patricia A. Hartz - updated : 9/21/2007
Victor A. McKusick - updated : 3/12/2007
Patricia A. Hartz - updated : 7/18/2006
Patricia A. Hartz - updated : 4/19/2005
Deborah L. Stone - updated : 11/15/2004
Victor A. McKusick - updated : 2/28/2003
Victor A. McKusick - updated : 7/2/2002
Victor A. McKusick - updated : 3/19/2001

Creation Date:
Ada Hamosh : 4/12/1999

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