* 604001

A-KINASE ANCHOR PROTEIN 9; AKAP9


Alternative titles; symbols

YOTIAO
A-KINASE ANCHOR PROTEIN, 450-KD; AKAP450
CENTROSOME- AND GOLGI-LOCALIZED PROTEIN KINASE N-ASSOCIATED PROTEIN; CGNAP


Other entities represented in this entry:

AKAP9/BRAF FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: AKAP9

Cytogenetic location: 7q21.2     Genomic coordinates (GRCh38): 7:91,940,862-92,110,673 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q21.2 ?Long QT syndrome 11 611820 AD 3

TEXT

Cloning and Expression

Proper synaptic function requires accurate localization of appropriate ion channels and neurotransmitter receptors to the postsynaptic site. This localization may occur by means of specific interactions between synaptic membrane proteins and a variety of anchoring or clustering molecules. Using a yeast 2-hybrid screen to identify proteins that interact with the intracellular C-terminal tail of the NMDA receptor NR1 subunit (GRIN1; 138249), Lin et al. (1998) isolated human brain cDNAs encoding a novel protein. The presumed full-length coding sequence encodes a predicted 1,642-amino acid protein containing many long coiled-coil regions throughout its length. Due to its coiled-coil structure, the authors named the protein 'yotiao,' after a popular Chinese breakfast food consisting of long strands of fried dough. The interaction of yotiao with NR1 is dependent upon the presence of the 37-amino acid region in the C-terminal tail of NR1 that is encoded by the alternatively spliced C1 exon cassette of NR1. Northern blot analysis of human tissues detected an 11-kb yotiao transcript that was expressed abundantly in skeletal muscle and pancreas, to a lesser degree in heart and placenta, and modestly in brain. Immunohistochemical experiments indicated that yotiao is expressed in a somatodendritic pattern in neurons throughout the rat brain, with prominent expression in the cerebral cortex, hippocampus, and cerebellum. The authors demonstrated that yotiao and NR1 are colocalized in rat brain. Yotiao is predominantly located at the neuromuscular junction in rat skeletal muscle. Biochemical studies showed that yotiao fractionates with cytoskeleton-associated proteins and with the postsynaptic density. Lin et al. (1998) concluded that yotiao is an NR1-binding protein that is potentially involved in the cytoskeletal attachment of NMDA receptors.

By overlay screening with RII (see 176910), database searches, and PCR of a Jurkat T-lymphocyte expression library, Witczak et al. (1999) cloned AKAP9, which they designated AKAP450. The deduced 3,908-amino acid protein has a calculated molecular mass of about 453 kD. The N-terminal 1,626 amino acids are identical to yotiao except for a 12-amino acid stretch not found in yotiao. The 2 proteins are alternatively spliced products of the AKAP9 gene. Northern blot analysis revealed a 12-kb transcript expressed in most tissues tested, with highest levels in kidney, intermediate levels in brain, heart, placenta, and lung, and low levels in skeletal muscle, liver, small intestine, and peripheral blood leukocytes. Prominent smearing suggested a high level of mRNA degradation. Hybridization with a more 3-prime probe revealed a transcript of about 8 kb that was prominently expressed in liver and kidney. Immunofluorescence localization showed staining of a single perinuclear dot in interphase HeLa cells and staining of 2 polarized dots in metaphase cells. Dual labeling of HeLa cells and Western blot analysis of purified centrosomes from a human lymphoblast cell line confirmed that AKAP9 localized to centrosomes. Western blot analysis revealed 4 distinct proteins in centrosome preparations, with the highest molecular mass protein migrating at about 450 kD.

Using the N-terminal region of protein kinase N (PKN; 601032) as bait in a yeast 2-hybrid screen of a brain cDNA library, Takahashi et al. (1999) cloned a fragment of AKAP9, which they designated CGNAP. They obtained the full-length cDNA by screening neuroblastoma and HeLa cell cDNA libraries and by RACE of a hippocampus cDNA library. The deduced 3,899-amino acid protein has a calculated molecular mass of about 452 kD. Takahashi et al. (1999) identified N- and C-terminal leucine zipper-like motifs and 2 central RII-binding motifs, as well as coiled-coil regions. Northern blot analysis revealed a 12-kb transcript ubiquitously expressed at low abundance.

By yeast 2-hybrid screening using Trax (602964) as bait, Bray et al. (2002) cloned Akap9 from a mouse testis cDNA library. Northern blot analysis of mouse tissues detected highest expression of a 14.5-kb transcript in spleen, skeletal muscle, and kidney. Upon overexposure, low levels were also detected in brain, heart, liver, lung, and testis. All tissues showed smearing of the Akap9 transcript. RT-PCR detected Akap9 in brain and testis and in all germ cell stages examined. Confocal microscopy of transfected NIH 3T3 mouse fibroblasts detected predominantly cytosolic localization of Akap9 and concentrated staining around the nucleus. Akap9 colocalized with Trax in a punctate perinuclear pattern.


Mapping

By genomic sequence analysis, Witczak et al. (1999) mapped the AKAP9 gene to chromosome 7q21-q22.


Gene Function

Regulation of NMDA receptor activity by kinases and phosphatases contributes to the modulation of synaptic transmission. Targeting of these enzymes near the substrate has been proposed to enhance phosphorylation-dependent modulation. Westphal et al. (1999) demonstrated that yotiao binds to both the type II regulatory subunit (e.g., 176910) of cAMP-dependent protein kinase (PKA), indicating that it is an A-kinase anchor protein (AKAP), and to type I protein phosphatase (PP1; e.g., 176875). The authors concluded that yotiao is a scaffold protein that physically attaches PP1 and PKA to NMDA receptors to regulate channel activity. By searching nucleotide databases and isolating cDNAs, Westphal et al. (1999) found that the yotiao gene is expressed as multiple alternatively spliced transcripts.

Witczak et al. (1999) determined that amino acids 2327 to 2602 of AKAP9 bind RII, and that a leu2556-to-pro mutation interfered with the interaction. Immunoprecipitation studies verified interaction between endogenous AKAP9 and RII in HeLa cells.

Takahashi et al. (1999) found that AKAP9 coimmunoprecipitated with the catalytic subunit of protein phosphatase-2A (see 176915) when the regulatory B subunit (see 604941) was exogenously expressed in COS-7 cells. AKAP9 also interacted with the catalytic subunit of protein phosphatase-1 in HeLa cells. Takahashi et al. (1999) showed that AKAP9 localized to centrosomes throughout the cell cycle, to the midbody at telophase, and to the Golgi apparatus at interphase, where a population of PKN and RII-alpha accumulated. They concluded that AKAP9 is a scaffolding protein that assembles several protein kinases and phosphatases on centrosomes and the Golgi apparatus, where physiologic events may be regulated by the phosphorylation state of specific protein substrates.

By yeast 2-hybrid analysis and in vitro binding assays, Bray et al. (2002) determined that Akap9 interacts directly with Trax.

I(Ks) is a slow heart potassium current carried by the I(Ks) potassium channel, critically important in the regulation of the cardiac action potential, particularly in the face of sympathetic nervous system stimulation. The I(Ks) potassium channel is a substrate for PKA phosphorylation in response to sympathetic nerve stimulation. The I(Ks) PKA macromolecular complex consists of an alpha subunit (KCNQ1; 607542), a regulatory subunit (KCNE1; 176261), and the AKAP yotiao, which binds to a leucine zipper motif in the KCNQ1 C terminus and in turn binds PKA and protein phosphatase-1. Disruption of this regulation by mutation in long QT syndrome (see 192500) is associated with elevated risk of sudden death. Kurokawa et al. (2004) studied the effects of the AKAP yotiao on the function of the I(Ks) channel that had been mutated to simulate channel phosphorylation, and they found direct AKAP-mediated alteration of channel function distinct from its role in the coordination of channel phosphorylation by PKA. These data revealed previously undescribed actions of yotiao that occur subsequent to channel phosphorylation and provided evidence that this adaptor protein also may serve as an effector in regulating this important ion channel.

Using RNA interference with human cell lines, Oshimori et al. (2009) found that knockdown of CGNAP led to failure of centrosomes to nucleate microtubules into astral arrays at the initiation of mitosis, abrogating spindle formation and proper alignment of chromosomes at the metaphase plate. Knockdown studies also revealed that CEP72 (616475) was required for localization of CGNAP to centrosomes and the Golgi apparatus.


Gene Structure

Witczak et al. (1999) determined that the AKAP9 gene contains 51 exons and spans more than 170 kb.


Cytogenetics

Ciampi et al. (2005) reported a BRAF (164757)-AKAP9 fusion gene created by paracentric inversion of chromosome 7q, resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contained the protein kinase domain and lacked the autoinhibitory N-terminal portion of BRAF. It had elevated kinase activity and transformed NIH 3T3 cells. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas (see 188550) developing after a short latency.


Molecular Genetics

Long QT Syndrome 11

Using GST pull-down and immunoprecipitation studies, Chen et al. (2007) identified 2 KCNQ1-binding domains in the AKAP9 gene, 1 on the N terminus and 1 on the C terminus. They analyzed the 8 exons encoding those 2 domains in 50 patients with LQTS who did not have mutations in any of the known LQTS genes and identified a missense mutation (S1570L; 604001.0001) in 1 patient (LQT11; 611820). The mutation, located in the C-terminal binding site, was not found in 1,320 reference alleles.

Modifier of Long QT Syndrome 1

In 349 members of a South African founder population of Afrikaner origin with long QT syndrome (LQT1; 192500), 168 of whom carried an identical-by-descent A341V mutation in the KCNQ1 gene (607542.0010), de Villiers et al. (2014) genotyped 4 SNPs in the AKAP9 gene (rs11772585, rs7808587, rs2282972, and rs2961024) and analyzed the association between phenotypic traits and alleles, genotypes, and haplotypes. The rs2961024 GG genotype, always represented by a homozygous CGCG haplotype (genotypes at all 4 SNPs), was significantly associated with an age-dependent QTc interval increase of 1% per additional 10 years, regardless of A341V mutation status. The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled the risk of cardiac events in the presence of A314V, and also increased disease severity. The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk, whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53%. De Villiers et al. (2014) stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 LONG QT SYNDROME 11 (1 family)

KCNQ1, SER1570LEU
  
RCV000006241...

In a 13-year-old Caucasian girl with long QT syndrome-11 (LQT11; 611820), Chen et al. (2007) identified heterozygosity for a ser1570-to-leu (S1570L) substitution in the AKAP9 gene, located in the C-terminal KCNQ1-binding region. The patient's father and 2 sisters had also been diagnosed with LQT syndrome; 1 sister who agreed to testing also carried the mutation, which was not found in 1,320 reference alleles. Functional studies indicated that the S1570L mutation reduced interaction between KCNQ1 and yotiao, reduced cAMP-induced phosphorylation of KCNQ1, and eliminated functional response of the I(Ks) channel to cAMP; a computational model of the ventricular cardiocyte showed prolongation of the action potential.


REFERENCES

  1. Bray, J. D., Chennathukuzhi, V. M., Hecht, N. B. Identification and characterization of cDNAs encoding four novel proteins that interact with translin associated factor-X. Genomics 79: 799-808, 2002. [PubMed: 12036294, related citations] [Full Text]

  2. Chen, L., Marquardt, M. L., Tester, D. J., Sampson, K. J., Ackerman, M. J., Kass, R. S. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc. Nat. Acad. Sci. 104: 20990-20995, 2007. [PubMed: 18093912, images, related citations] [Full Text]

  3. Ciampi, R., Knauf, J. A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M. N., Rabes, H. M., Fagin, J. A., Nikiforov, Y. E. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Invest. 115: 94-101, 2005. [PubMed: 15630448, images, related citations] [Full Text]

  4. de Villiers, C. P., van der Merwe, L., Crotti, L., Goosen, A., George, A. L., Schwartz, P. J., Brink, P. A., Moolman-Smook, J. C., Corfield, V. A. AKAP9 is a genetic modifier of congenital long-QT syndrome type 1. Circ. Cardiovasc. Genet. 7: 599-606, 2014. [PubMed: 25087618, images, related citations] [Full Text]

  5. Kurokawa, J., Motoike, H. K., Rao, J., Kass, R. S. Regulatory actions of the A-kinase anchoring protein yotiao on a heart potassium channel downstream of PKA phosphorylation. Proc. Nat. Acad. Sci. 101: 16374-16378, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 101: 17884 only, 2004. [PubMed: 15528278, images, related citations] [Full Text]

  6. Lin, J. W., Wyszynski, M., Madhavan, R., Sealock, R., Kim, J. U., Sheng, M. Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J. Neurosci. 18: 2017-2027, 1998. [PubMed: 9482789, related citations] [Full Text]

  7. Oshimori, N., Li, X., Ohsugi, M., Yamamoto, T. Cep72 regulates the localization of key centrosomal proteins and proper bipolar spindle formation. EMBO J. 28: 2066-2076, 2009. [PubMed: 19536135, images, related citations] [Full Text]

  8. Takahashi, M., Shibata, H., Shimakawa, M., Miyamoto, M., Mukai, H., Ono, Y. Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the Golgi apparatus. J. Biol. Chem. 274: 17267-17274, 1999. [PubMed: 10358086, related citations] [Full Text]

  9. Westphal, R. S., Tavalin, S. J., Lin, J. W., Alto, N. M., Fraser, I. D. C., Langeberg, L. K., Sheng, M., Scott, J. D. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science 285: 93-96, 1999. [PubMed: 10390370, related citations] [Full Text]

  10. Witczak, O., Skalhegg, B. S., Keryer, G., Bornens, M., Tasken, K., Jahnsen, T., Orstavik, S. Cloning and characterization of a cDNA encoding an A-kinase anchoring protein located in the centrosome, AKAP450. EMBO J. 18: 1858-1868, 1999. [PubMed: 10202149, related citations] [Full Text]


Marla J. F. O'Neill - updated : 05/02/2017
Patricia A. Hartz - updated : 7/20/2015
Marla J. F. O'Neill - updated : 2/12/2008
Marla J. F. O'Neill - updated : 2/2/2005
Victor A. McKusick - updated : 12/30/2004
Patricia A. Hartz - updated : 4/23/2003
Patricia A. Hartz - updated : 4/21/2003
Creation Date:
Patti M. Sherman : 7/9/1999
alopez : 05/02/2017
carol : 07/22/2015
carol : 7/21/2015
mgross : 7/20/2015
mcolton : 7/20/2015
terry : 6/4/2012
wwang : 2/26/2008
terry : 2/12/2008
terry : 6/28/2005
tkritzer : 2/3/2005
terry : 2/2/2005
tkritzer : 1/24/2005
terry : 12/30/2004
terry : 12/30/2004
terry : 7/20/2004
mgross : 4/29/2003
mgross : 4/28/2003
mgross : 4/28/2003
terry : 4/23/2003
terry : 4/21/2003
mgross : 9/21/1999
mgross : 7/29/1999
psherman : 7/26/1999

* 604001

A-KINASE ANCHOR PROTEIN 9; AKAP9


Alternative titles; symbols

YOTIAO
A-KINASE ANCHOR PROTEIN, 450-KD; AKAP450
CENTROSOME- AND GOLGI-LOCALIZED PROTEIN KINASE N-ASSOCIATED PROTEIN; CGNAP


Other entities represented in this entry:

AKAP9/BRAF FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: AKAP9

Cytogenetic location: 7q21.2     Genomic coordinates (GRCh38): 7:91,940,862-92,110,673 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
7q21.2 ?Long QT syndrome 11 611820 Autosomal dominant 3

TEXT

Cloning and Expression

Proper synaptic function requires accurate localization of appropriate ion channels and neurotransmitter receptors to the postsynaptic site. This localization may occur by means of specific interactions between synaptic membrane proteins and a variety of anchoring or clustering molecules. Using a yeast 2-hybrid screen to identify proteins that interact with the intracellular C-terminal tail of the NMDA receptor NR1 subunit (GRIN1; 138249), Lin et al. (1998) isolated human brain cDNAs encoding a novel protein. The presumed full-length coding sequence encodes a predicted 1,642-amino acid protein containing many long coiled-coil regions throughout its length. Due to its coiled-coil structure, the authors named the protein 'yotiao,' after a popular Chinese breakfast food consisting of long strands of fried dough. The interaction of yotiao with NR1 is dependent upon the presence of the 37-amino acid region in the C-terminal tail of NR1 that is encoded by the alternatively spliced C1 exon cassette of NR1. Northern blot analysis of human tissues detected an 11-kb yotiao transcript that was expressed abundantly in skeletal muscle and pancreas, to a lesser degree in heart and placenta, and modestly in brain. Immunohistochemical experiments indicated that yotiao is expressed in a somatodendritic pattern in neurons throughout the rat brain, with prominent expression in the cerebral cortex, hippocampus, and cerebellum. The authors demonstrated that yotiao and NR1 are colocalized in rat brain. Yotiao is predominantly located at the neuromuscular junction in rat skeletal muscle. Biochemical studies showed that yotiao fractionates with cytoskeleton-associated proteins and with the postsynaptic density. Lin et al. (1998) concluded that yotiao is an NR1-binding protein that is potentially involved in the cytoskeletal attachment of NMDA receptors.

By overlay screening with RII (see 176910), database searches, and PCR of a Jurkat T-lymphocyte expression library, Witczak et al. (1999) cloned AKAP9, which they designated AKAP450. The deduced 3,908-amino acid protein has a calculated molecular mass of about 453 kD. The N-terminal 1,626 amino acids are identical to yotiao except for a 12-amino acid stretch not found in yotiao. The 2 proteins are alternatively spliced products of the AKAP9 gene. Northern blot analysis revealed a 12-kb transcript expressed in most tissues tested, with highest levels in kidney, intermediate levels in brain, heart, placenta, and lung, and low levels in skeletal muscle, liver, small intestine, and peripheral blood leukocytes. Prominent smearing suggested a high level of mRNA degradation. Hybridization with a more 3-prime probe revealed a transcript of about 8 kb that was prominently expressed in liver and kidney. Immunofluorescence localization showed staining of a single perinuclear dot in interphase HeLa cells and staining of 2 polarized dots in metaphase cells. Dual labeling of HeLa cells and Western blot analysis of purified centrosomes from a human lymphoblast cell line confirmed that AKAP9 localized to centrosomes. Western blot analysis revealed 4 distinct proteins in centrosome preparations, with the highest molecular mass protein migrating at about 450 kD.

Using the N-terminal region of protein kinase N (PKN; 601032) as bait in a yeast 2-hybrid screen of a brain cDNA library, Takahashi et al. (1999) cloned a fragment of AKAP9, which they designated CGNAP. They obtained the full-length cDNA by screening neuroblastoma and HeLa cell cDNA libraries and by RACE of a hippocampus cDNA library. The deduced 3,899-amino acid protein has a calculated molecular mass of about 452 kD. Takahashi et al. (1999) identified N- and C-terminal leucine zipper-like motifs and 2 central RII-binding motifs, as well as coiled-coil regions. Northern blot analysis revealed a 12-kb transcript ubiquitously expressed at low abundance.

By yeast 2-hybrid screening using Trax (602964) as bait, Bray et al. (2002) cloned Akap9 from a mouse testis cDNA library. Northern blot analysis of mouse tissues detected highest expression of a 14.5-kb transcript in spleen, skeletal muscle, and kidney. Upon overexposure, low levels were also detected in brain, heart, liver, lung, and testis. All tissues showed smearing of the Akap9 transcript. RT-PCR detected Akap9 in brain and testis and in all germ cell stages examined. Confocal microscopy of transfected NIH 3T3 mouse fibroblasts detected predominantly cytosolic localization of Akap9 and concentrated staining around the nucleus. Akap9 colocalized with Trax in a punctate perinuclear pattern.


Mapping

By genomic sequence analysis, Witczak et al. (1999) mapped the AKAP9 gene to chromosome 7q21-q22.


Gene Function

Regulation of NMDA receptor activity by kinases and phosphatases contributes to the modulation of synaptic transmission. Targeting of these enzymes near the substrate has been proposed to enhance phosphorylation-dependent modulation. Westphal et al. (1999) demonstrated that yotiao binds to both the type II regulatory subunit (e.g., 176910) of cAMP-dependent protein kinase (PKA), indicating that it is an A-kinase anchor protein (AKAP), and to type I protein phosphatase (PP1; e.g., 176875). The authors concluded that yotiao is a scaffold protein that physically attaches PP1 and PKA to NMDA receptors to regulate channel activity. By searching nucleotide databases and isolating cDNAs, Westphal et al. (1999) found that the yotiao gene is expressed as multiple alternatively spliced transcripts.

Witczak et al. (1999) determined that amino acids 2327 to 2602 of AKAP9 bind RII, and that a leu2556-to-pro mutation interfered with the interaction. Immunoprecipitation studies verified interaction between endogenous AKAP9 and RII in HeLa cells.

Takahashi et al. (1999) found that AKAP9 coimmunoprecipitated with the catalytic subunit of protein phosphatase-2A (see 176915) when the regulatory B subunit (see 604941) was exogenously expressed in COS-7 cells. AKAP9 also interacted with the catalytic subunit of protein phosphatase-1 in HeLa cells. Takahashi et al. (1999) showed that AKAP9 localized to centrosomes throughout the cell cycle, to the midbody at telophase, and to the Golgi apparatus at interphase, where a population of PKN and RII-alpha accumulated. They concluded that AKAP9 is a scaffolding protein that assembles several protein kinases and phosphatases on centrosomes and the Golgi apparatus, where physiologic events may be regulated by the phosphorylation state of specific protein substrates.

By yeast 2-hybrid analysis and in vitro binding assays, Bray et al. (2002) determined that Akap9 interacts directly with Trax.

I(Ks) is a slow heart potassium current carried by the I(Ks) potassium channel, critically important in the regulation of the cardiac action potential, particularly in the face of sympathetic nervous system stimulation. The I(Ks) potassium channel is a substrate for PKA phosphorylation in response to sympathetic nerve stimulation. The I(Ks) PKA macromolecular complex consists of an alpha subunit (KCNQ1; 607542), a regulatory subunit (KCNE1; 176261), and the AKAP yotiao, which binds to a leucine zipper motif in the KCNQ1 C terminus and in turn binds PKA and protein phosphatase-1. Disruption of this regulation by mutation in long QT syndrome (see 192500) is associated with elevated risk of sudden death. Kurokawa et al. (2004) studied the effects of the AKAP yotiao on the function of the I(Ks) channel that had been mutated to simulate channel phosphorylation, and they found direct AKAP-mediated alteration of channel function distinct from its role in the coordination of channel phosphorylation by PKA. These data revealed previously undescribed actions of yotiao that occur subsequent to channel phosphorylation and provided evidence that this adaptor protein also may serve as an effector in regulating this important ion channel.

Using RNA interference with human cell lines, Oshimori et al. (2009) found that knockdown of CGNAP led to failure of centrosomes to nucleate microtubules into astral arrays at the initiation of mitosis, abrogating spindle formation and proper alignment of chromosomes at the metaphase plate. Knockdown studies also revealed that CEP72 (616475) was required for localization of CGNAP to centrosomes and the Golgi apparatus.


Gene Structure

Witczak et al. (1999) determined that the AKAP9 gene contains 51 exons and spans more than 170 kb.


Cytogenetics

Ciampi et al. (2005) reported a BRAF (164757)-AKAP9 fusion gene created by paracentric inversion of chromosome 7q, resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contained the protein kinase domain and lacked the autoinhibitory N-terminal portion of BRAF. It had elevated kinase activity and transformed NIH 3T3 cells. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas (see 188550) developing after a short latency.


Molecular Genetics

Long QT Syndrome 11

Using GST pull-down and immunoprecipitation studies, Chen et al. (2007) identified 2 KCNQ1-binding domains in the AKAP9 gene, 1 on the N terminus and 1 on the C terminus. They analyzed the 8 exons encoding those 2 domains in 50 patients with LQTS who did not have mutations in any of the known LQTS genes and identified a missense mutation (S1570L; 604001.0001) in 1 patient (LQT11; 611820). The mutation, located in the C-terminal binding site, was not found in 1,320 reference alleles.

Modifier of Long QT Syndrome 1

In 349 members of a South African founder population of Afrikaner origin with long QT syndrome (LQT1; 192500), 168 of whom carried an identical-by-descent A341V mutation in the KCNQ1 gene (607542.0010), de Villiers et al. (2014) genotyped 4 SNPs in the AKAP9 gene (rs11772585, rs7808587, rs2282972, and rs2961024) and analyzed the association between phenotypic traits and alleles, genotypes, and haplotypes. The rs2961024 GG genotype, always represented by a homozygous CGCG haplotype (genotypes at all 4 SNPs), was significantly associated with an age-dependent QTc interval increase of 1% per additional 10 years, regardless of A341V mutation status. The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled the risk of cardiac events in the presence of A314V, and also increased disease severity. The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk, whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53%. De Villiers et al. (2014) stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects.


ALLELIC VARIANTS 1 Selected Example):

.0001   LONG QT SYNDROME 11 (1 family)

KCNQ1, SER1570LEU
SNP: rs121908566, gnomAD: rs121908566, ClinVar: RCV000006241, RCV000631713, RCV000756981, RCV002336077

In a 13-year-old Caucasian girl with long QT syndrome-11 (LQT11; 611820), Chen et al. (2007) identified heterozygosity for a ser1570-to-leu (S1570L) substitution in the AKAP9 gene, located in the C-terminal KCNQ1-binding region. The patient's father and 2 sisters had also been diagnosed with LQT syndrome; 1 sister who agreed to testing also carried the mutation, which was not found in 1,320 reference alleles. Functional studies indicated that the S1570L mutation reduced interaction between KCNQ1 and yotiao, reduced cAMP-induced phosphorylation of KCNQ1, and eliminated functional response of the I(Ks) channel to cAMP; a computational model of the ventricular cardiocyte showed prolongation of the action potential.


REFERENCES

  1. Bray, J. D., Chennathukuzhi, V. M., Hecht, N. B. Identification and characterization of cDNAs encoding four novel proteins that interact with translin associated factor-X. Genomics 79: 799-808, 2002. [PubMed: 12036294] [Full Text: https://doi.org/10.1006/geno.2002.6779]

  2. Chen, L., Marquardt, M. L., Tester, D. J., Sampson, K. J., Ackerman, M. J., Kass, R. S. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc. Nat. Acad. Sci. 104: 20990-20995, 2007. [PubMed: 18093912] [Full Text: https://doi.org/10.1073/pnas.0710527105]

  3. Ciampi, R., Knauf, J. A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M. N., Rabes, H. M., Fagin, J. A., Nikiforov, Y. E. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J. Clin. Invest. 115: 94-101, 2005. [PubMed: 15630448] [Full Text: https://doi.org/10.1172/JCI23237]

  4. de Villiers, C. P., van der Merwe, L., Crotti, L., Goosen, A., George, A. L., Schwartz, P. J., Brink, P. A., Moolman-Smook, J. C., Corfield, V. A. AKAP9 is a genetic modifier of congenital long-QT syndrome type 1. Circ. Cardiovasc. Genet. 7: 599-606, 2014. [PubMed: 25087618] [Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000580]

  5. Kurokawa, J., Motoike, H. K., Rao, J., Kass, R. S. Regulatory actions of the A-kinase anchoring protein yotiao on a heart potassium channel downstream of PKA phosphorylation. Proc. Nat. Acad. Sci. 101: 16374-16378, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 101: 17884 only, 2004. [PubMed: 15528278] [Full Text: https://doi.org/10.1073/pnas.0405583101]

  6. Lin, J. W., Wyszynski, M., Madhavan, R., Sealock, R., Kim, J. U., Sheng, M. Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J. Neurosci. 18: 2017-2027, 1998. [PubMed: 9482789] [Full Text: https://doi.org/10.1523/JNEUROSCI.18-06-02017.1998]

  7. Oshimori, N., Li, X., Ohsugi, M., Yamamoto, T. Cep72 regulates the localization of key centrosomal proteins and proper bipolar spindle formation. EMBO J. 28: 2066-2076, 2009. [PubMed: 19536135] [Full Text: https://doi.org/10.1038/emboj.2009.161]

  8. Takahashi, M., Shibata, H., Shimakawa, M., Miyamoto, M., Mukai, H., Ono, Y. Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the Golgi apparatus. J. Biol. Chem. 274: 17267-17274, 1999. [PubMed: 10358086] [Full Text: https://doi.org/10.1074/jbc.274.24.17267]

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Contributors:
Marla J. F. O'Neill - updated : 05/02/2017
Patricia A. Hartz - updated : 7/20/2015
Marla J. F. O'Neill - updated : 2/12/2008
Marla J. F. O'Neill - updated : 2/2/2005
Victor A. McKusick - updated : 12/30/2004
Patricia A. Hartz - updated : 4/23/2003
Patricia A. Hartz - updated : 4/21/2003

Creation Date:
Patti M. Sherman : 7/9/1999

Edit History:
alopez : 05/02/2017
carol : 07/22/2015
carol : 7/21/2015
mgross : 7/20/2015
mcolton : 7/20/2015
terry : 6/4/2012
wwang : 2/26/2008
terry : 2/12/2008
terry : 6/28/2005
tkritzer : 2/3/2005
terry : 2/2/2005
tkritzer : 1/24/2005
terry : 12/30/2004
terry : 12/30/2004
terry : 7/20/2004
mgross : 4/29/2003
mgross : 4/28/2003
mgross : 4/28/2003
terry : 4/23/2003
terry : 4/21/2003
mgross : 9/21/1999
mgross : 7/29/1999
psherman : 7/26/1999