* 103020

ADENYLATE KINASE 2; AK2


Alternative titles; symbols

ADENYLATE KINASE, MITOCHONDRIAL MYOKINASE


HGNC Approved Gene Symbol: AK2

Cytogenetic location: 1p35.1     Genomic coordinates (GRCh38): 1:33,007,940-33,036,883 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p35.1 Reticular dysgenesis 267500 AR 3

TEXT

Description

Nucleoside monophosphate kinases, including adenylate kinases, catalyze the reversible phosphorylation between nucleoside triphosphates and monophosphates.


Cloning and Expression

Bruns and Regina (1977) analyzed the subcellular compartmentalization of adenylate kinase-2 (EC 2.7.4.3) in HeLa cells, mouse RAG cells, and RAG-human hybrids expressing human AK2. The results indicated that AK2 is a mitochondrial enzyme.

Noma et al. (1998) isolated cDNAs encoding human adenylate kinase-2 from a HeLa cell cDNA library, using bovine AK2 cDNA as probe. Two transcripts were identified: one, designated AK2A, encodes a deduced 239-amino acid protein with a predicted molecular mass of 26.5 kD, and the other, designated AK2B, encodes a deduced 232-amino acid protein with a predicted molecular mass of 25.6 kD. Northern blot analysis demonstrated 3 strong hybridizing signals of 0.9 (AK2A), 1.7 (AK2B), and 3.5 kb, with high expression in liver, heart, skeletal muscle, and pancreas, moderate expression in kidney, placenta, and brain, and weak expression in lung. However, Western blot analysis showed high levels of AK2 protein in liver, heart, and kidney, low levels in lung, and undetectable levels in brain and skeletal muscle.


Mapping

The existence of a second adenylate kinase locus linked to PGM1 and peptidase C, i.e., on chromosome 1, was suggested by cell hybridization studies by Nguyen et al. (1972). The Goss-Harris method of mapping combines features of recombinational study in families and synteny tests in hybrid cells. As applied to chromosome 1, the method shows that AK2 and UMPK are distal to PGM1 and that the order of the loci is PGM1: UMPK: (AK2, alpha-FUC): ENO1 (Goss and Harris, 1977). Carritt et al. (1982) presented evidence that AK2 is in 1p34.


Gene Function

Lee et al. (2007) showed that intrinsic apoptosis in human cells that was induced by the chemotherapeutic agent etoposide or the antibiotic staurosporine, but not by FAS ligand (TNFSF6; 134638) or TRAIL (TNFSF10; 603598), caused translocation of AK2 from mitochondria to the cytoplasm, followed by formation of a complex between AK2, FADD (602457), and CASP10 (601762). Yeast 2-hybrid analysis, protein pull-down assays, and immunoprecipitation analysis showed that the N- and C-terminal domains of AK2, which include nucleoside- and substrate-binding domains, respectively, bound the C-terminal death domain of FADD. AK2 binding promoted association of CASP10 with FADD, and addition of purified AK2 protein to cell extracts induced activation of CASP10 via FADD, leading to subsequent activation of CASP9 (602234) and CASP3 (600636). Apoptosis through the AK2 complex did not correlate with the adenylate kinase activity of AK2, did not require CASP8 (601763)-mediated apoptotic responses, and did not involve mitochondrial cytochrome c release. Immunodepletion or knockdown of AK2, FADD, or CASP10 abrogated etoposide-induced apoptosis, and AK2 complexes were not observed in several etoposide-resistant human tumor cell lines that were deficient in expression of FADD, CASP10, or CASP3. In contrast to the findings in human cells, etoposide-induced apoptosis was observed in mouse embryonic fibroblasts that lacked Fadd expression. Since mice also lack Casp10, Lee et al. (2007) concluded that mice lack an apoptotic pathway comparable to the AK2-FADD-CASP10 pathway in humans.

Pannicke et al. (2009) showed that knockdown of zebrafish ak2 also leads to aberrant leukocyte development, demonstrating the evolutionarily conserved role of AK2. They concluded that their results provide in vivo evidence for AK2 selectivity in leukocyte differentiation.

Kim et al. (2014) found that human AK2 and DUSP26 (618368) formed a complex and that AK2 promoted dephosphorylation of FADD by DUSP26. AK2 enhanced the interaction between DUSP26 and FADD independently of its adenylate kinase activity. Enhanced AK2 expression promoted DUSP26 dephosphorylation of FADD and inhibited cell proliferation and tumorigenicity. Conversely, reduced AK2 expression increased FADD phosphorylation and promoted cell proliferation and tumorigenicity.


Molecular Genetics

In 6 affected individuals from 5 families segregating reticular dysgenesis (267500), Pannicke et al. (2009) identified 6 causative mutations in homozygous or compound heterozygous state (103020.0001-103020.0006).

Lagresle-Peyrou et al. (2009) identified biallelic mutations in AK2 (103020.0007-103020.0013) in 7 individuals with reticular dysgenesis. These mutations resulted in absent or strongly decreased protein expression. The authors then demonstrated that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Finally, Lagresle-Peyrou et al. (2009) established that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation for the sensorineural deafness in these individuals. Lagresle-Peyrou et al. (2009) concluded that their results identified a previously unknown mechanism involved in regulation of hematopoietic cell differentiation in one of the most severe human immunodeficiency syndromes.


ALLELIC VARIANTS ( 13 Selected Examples):

.0001 RETICULAR DYSGENESIS

AK2, 5,038-BP DEL
   RCV000019912

In a German male with reticular dysgenesis (267500), Pannicke et al. (2009) identified a homozygous 5,038-bp deletion encompassing parts of exon 6, all of intron 6 and parts of exon 7 reaching into the 3-prime UTR of the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0002 RETICULAR DYSGENESIS

AK2, 1-BP DEL, 118T
  
RCV000019913

In a German male with reticular dysgenesis (267500), Pannicke et al. (2009) identified compound heterozygosity for 2 mutations in the AK2 gene: a 1-bp deletion (118delT) leading to a frameshift and premature termination, and a 1A-G transition leading to a met1-to-val (M1V) substitution (103020.0003). The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. Each parent was heterozygous for one of the mutations. The mutations were not found in 112 German or 50 Turkish healthy subjects.


.0003 RETICULAR DYSGENESIS

AK2, MET1VAL
  
RCV000019914

For discussion of the met1-to-val (M1V) mutation in the AK2 gene that was found in compound heterozygous state in a patient with reticular dysgenesis (267500) by Pannicke et al. (2009), see 103020.0002.


.0004 RETICULAR DYSGENESIS

AK2, 331, G-A, -1
  
RCV000019915

In a German male with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a splicing mutation, 331-1G-A, in the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0005 RETICULAR DYSGENESIS

AK2, 1-BP DEL, 453C
  
RCV000019916...

In male and female Turkish sibs with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a 1-bp deletion (453delC) in the AK2 gene, leading to a frameshift and premature termination. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0006 RETICULAR DYSGENESIS

AK2, 498, G-A, +1
  
RCV000019917...

In a Turkish female with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a splicing mutation, 498+1G-A, in the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0007 RETICULAR DYSGENESIS

AK2, ASP165GLY
  
RCV000019918

In 2 separate pedigrees with reticular dysgenesis (267500), each of whom was consanguineous, Lagresle-Peyrou et al. (2009) identified homozygosity for an A-to-G transition at nucleotide 546 in exon 5 of the AK2 gene, resulting in an asp-to-gly substitution in codon 165 (D165G) within the LID domain. This mutation changed a highly conserved amino acid. The parents were found to be carriers, and unaffected sibs were heterozygous or homozygous for the wildtype allele.


.0008 RETICULAR DYSGENESIS

AK2, LEU183TER
  
RCV000019919

In a female from a consanguineous family affected with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified a 1-bp deletion of C at nucleotide 523 in exon 6 of the AK2 gene (523delC), resulting in a substitution of a termination codon for a leucine at codon 183 (L183X). This mutation was not detected in her sister, and each parent was found to be a carrier.


.0009 RETICULAR DYSGENESIS

AK2, ARG186CYS
  
RCV000019920...

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) found compound heterozygosity for mutations in the AK2 gene: a C-to-T transition at nucleotide 556 in exon 6, resulting in an arg-to-cys substitution at codon 186 (R186C), and an exon 2 deletion (see 103020.0010).


.0010 RETICULAR DYSGENESIS

AK2, EX2 DEL
   RCV000019921

In a female with reticular dysgenesis (267500) from a nonconsanguineous family, Lagresle-Peyrou et al. (2009) identified compound heterozygosity for deletion of exon 2 of the AK2 gene and an arg186-to-cys substitution (103020.0009). Each parent was a carrier of one of the mutations.


.0011 RETICULAR DYSGENESIS

AK2, ARG103TRP
  
RCV000019922

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified a C-to-T transition at nucleotide 307 in exon 3 of the AK2 gene, resulting in an arg-to-trp substitution at codon 103 (R103W). Each of her parents was a carrier for this mutation, which occurs in a highly conserved amino acid residue.


.0012 RETICULAR DYSGENESIS

AK2, LYS233TER
  
RCV000019923

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified a 5-kb deletion following nucleotide 633 (633del5kb), resulting in a lys-to-ter substitution at codon 233 (K233X). The patient was homozygous for this mutation. Two of her 3 unaffected sibs, and each of her unaffected parents, were carriers.


.0013 RETICULAR DYSGENESIS

AK2, GLU9TER
  
RCV000019924

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified homozygosity for a G-to-T transversion at nucleotide 25 in exon 1 of the AK2 gene, resulting in a glu-to-ter codon substitution at amino acid 9 (E9X). The child was homozygous for this mutation. Each of her parents was a carrier.


REFERENCES

  1. Bruns, G. A. P., Regina, V. M. Adenylate kinase-2, a mitochondrial enzyme. Biochem. Genet. 15: 477-486, 1977. [PubMed: 195572, related citations] [Full Text]

  2. Carritt, B., King, J., Welch, H. M. Gene order and localization of enzyme loci on the short arm of chromosome 1. Ann. Hum. Genet. 46: 329-335, 1982. [PubMed: 6961883, related citations] [Full Text]

  3. Goss, S. J., Harris, H. Gene transfer by means of cell fusion. II. The mapping of 8 loci on human chromosome 1 by statistical analysis of gene assortment in somatic cell hybrids. J. Cell Sci. 25: 39-57, 1977. [PubMed: 561097, related citations] [Full Text]

  4. Kim, H., Lee, H.-J., Oh, Y., Choi, S.-G., Hong, S.-H., Kim, H.-J., Lee, S.-Y., Choi, J.-W., Hwang, D. S., Kim, K.-S., Kim, H.-J., Zhang, J., Youn, H.-J., Noh, D.-Y., Jung, Y.-K. The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth. Nature Commun. 5: 3351, 2014. Note: Electronic Article. [PubMed: 24548998, images, related citations] [Full Text]

  5. Lagresle-Peyrou, C., Six, E. M., Picard, C., Rieux-Laucat, F., Michel, V., Ditadi, A., Chappedelaine, C. D., Morillon, E., Valensi, F., Simon-Stoos, K. L., Mullikin, J. C., Noroski, L. M., and 10 others. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nature Genet. 41: 106-111, 2009. [PubMed: 19043416, images, related citations] [Full Text]

  6. Lee, H.-J., Pyo, J.-O., Oh, Y., Kim, H.-J., Hong, S., Jeon, Y.-J., Kim, H., Cho, D.-H., Woo, H.-N., Song, S., Nam, J.-H., Kim, H. J., Kim, K.-S., Jung, Y.-K. AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10. Nature Cell Biol. 9: 1303-1310, 2007. [PubMed: 17952061, related citations] [Full Text]

  7. Nguyen, V. C., Billardon, C., Rebourcet, R., Kaouel, C. L.-B., Picard, J. Y., Weil, D., Frezal, J. The existence of a second adenylate kinase locus linked to PGM-1 and peptidase-C. Ann. Genet. 15: 213-218, 1972. [PubMed: 4539479, related citations]

  8. Noma, T., Song, S., Yoon, Y.-S., Tanaka, S., Nakazawa, A. cDNA cloning and tissue-specific expression of the gene encoding human adenylate kinase isozyme 2. Biochim. Biophys. Acta 1395: 34-39, 1998. [PubMed: 9434148, related citations] [Full Text]

  9. Pannicke, U., Honig, M., Hess, I., Friesen, C., Holzmann, K., Rump, E.-M., Barth, T. F., Rojewski, M. T., Schulz, A., Boehm, T., Friedrich, W., Schwarz, K. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nature Genet. 41: 101-105, 2009. [PubMed: 19043417, related citations] [Full Text]


Bao Lige - updated : 03/27/2019
Ada Hamosh - updated : 1/15/2010
Ada Hamosh - updated : 8/4/2009
Patricia A. Hartz - updated : 10/28/2008
Carol A. Bocchini - updated : 8/6/2003
Creation Date:
Victor A. McKusick : 6/4/1986
carol : 09/19/2022
carol : 03/28/2019
mgross : 03/27/2019
mcolton : 08/03/2015
terry : 6/11/2012
alopez : 1/26/2010
terry : 1/15/2010
terry : 8/13/2009
carol : 8/12/2009
terry : 8/4/2009
mgross : 10/28/2008
ckniffin : 6/1/2004
tkritzer : 8/8/2003
carol : 8/6/2003
psherman : 4/15/1998
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988
reenie : 2/9/1987
marie : 1/7/1987

* 103020

ADENYLATE KINASE 2; AK2


Alternative titles; symbols

ADENYLATE KINASE, MITOCHONDRIAL MYOKINASE


HGNC Approved Gene Symbol: AK2

SNOMEDCT: 111584000;  


Cytogenetic location: 1p35.1     Genomic coordinates (GRCh38): 1:33,007,940-33,036,883 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p35.1 Reticular dysgenesis 267500 Autosomal recessive 3

TEXT

Description

Nucleoside monophosphate kinases, including adenylate kinases, catalyze the reversible phosphorylation between nucleoside triphosphates and monophosphates.


Cloning and Expression

Bruns and Regina (1977) analyzed the subcellular compartmentalization of adenylate kinase-2 (EC 2.7.4.3) in HeLa cells, mouse RAG cells, and RAG-human hybrids expressing human AK2. The results indicated that AK2 is a mitochondrial enzyme.

Noma et al. (1998) isolated cDNAs encoding human adenylate kinase-2 from a HeLa cell cDNA library, using bovine AK2 cDNA as probe. Two transcripts were identified: one, designated AK2A, encodes a deduced 239-amino acid protein with a predicted molecular mass of 26.5 kD, and the other, designated AK2B, encodes a deduced 232-amino acid protein with a predicted molecular mass of 25.6 kD. Northern blot analysis demonstrated 3 strong hybridizing signals of 0.9 (AK2A), 1.7 (AK2B), and 3.5 kb, with high expression in liver, heart, skeletal muscle, and pancreas, moderate expression in kidney, placenta, and brain, and weak expression in lung. However, Western blot analysis showed high levels of AK2 protein in liver, heart, and kidney, low levels in lung, and undetectable levels in brain and skeletal muscle.


Mapping

The existence of a second adenylate kinase locus linked to PGM1 and peptidase C, i.e., on chromosome 1, was suggested by cell hybridization studies by Nguyen et al. (1972). The Goss-Harris method of mapping combines features of recombinational study in families and synteny tests in hybrid cells. As applied to chromosome 1, the method shows that AK2 and UMPK are distal to PGM1 and that the order of the loci is PGM1: UMPK: (AK2, alpha-FUC): ENO1 (Goss and Harris, 1977). Carritt et al. (1982) presented evidence that AK2 is in 1p34.


Gene Function

Lee et al. (2007) showed that intrinsic apoptosis in human cells that was induced by the chemotherapeutic agent etoposide or the antibiotic staurosporine, but not by FAS ligand (TNFSF6; 134638) or TRAIL (TNFSF10; 603598), caused translocation of AK2 from mitochondria to the cytoplasm, followed by formation of a complex between AK2, FADD (602457), and CASP10 (601762). Yeast 2-hybrid analysis, protein pull-down assays, and immunoprecipitation analysis showed that the N- and C-terminal domains of AK2, which include nucleoside- and substrate-binding domains, respectively, bound the C-terminal death domain of FADD. AK2 binding promoted association of CASP10 with FADD, and addition of purified AK2 protein to cell extracts induced activation of CASP10 via FADD, leading to subsequent activation of CASP9 (602234) and CASP3 (600636). Apoptosis through the AK2 complex did not correlate with the adenylate kinase activity of AK2, did not require CASP8 (601763)-mediated apoptotic responses, and did not involve mitochondrial cytochrome c release. Immunodepletion or knockdown of AK2, FADD, or CASP10 abrogated etoposide-induced apoptosis, and AK2 complexes were not observed in several etoposide-resistant human tumor cell lines that were deficient in expression of FADD, CASP10, or CASP3. In contrast to the findings in human cells, etoposide-induced apoptosis was observed in mouse embryonic fibroblasts that lacked Fadd expression. Since mice also lack Casp10, Lee et al. (2007) concluded that mice lack an apoptotic pathway comparable to the AK2-FADD-CASP10 pathway in humans.

Pannicke et al. (2009) showed that knockdown of zebrafish ak2 also leads to aberrant leukocyte development, demonstrating the evolutionarily conserved role of AK2. They concluded that their results provide in vivo evidence for AK2 selectivity in leukocyte differentiation.

Kim et al. (2014) found that human AK2 and DUSP26 (618368) formed a complex and that AK2 promoted dephosphorylation of FADD by DUSP26. AK2 enhanced the interaction between DUSP26 and FADD independently of its adenylate kinase activity. Enhanced AK2 expression promoted DUSP26 dephosphorylation of FADD and inhibited cell proliferation and tumorigenicity. Conversely, reduced AK2 expression increased FADD phosphorylation and promoted cell proliferation and tumorigenicity.


Molecular Genetics

In 6 affected individuals from 5 families segregating reticular dysgenesis (267500), Pannicke et al. (2009) identified 6 causative mutations in homozygous or compound heterozygous state (103020.0001-103020.0006).

Lagresle-Peyrou et al. (2009) identified biallelic mutations in AK2 (103020.0007-103020.0013) in 7 individuals with reticular dysgenesis. These mutations resulted in absent or strongly decreased protein expression. The authors then demonstrated that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Finally, Lagresle-Peyrou et al. (2009) established that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation for the sensorineural deafness in these individuals. Lagresle-Peyrou et al. (2009) concluded that their results identified a previously unknown mechanism involved in regulation of hematopoietic cell differentiation in one of the most severe human immunodeficiency syndromes.


ALLELIC VARIANTS 13 Selected Examples):

.0001   RETICULAR DYSGENESIS

AK2, 5,038-BP DEL
ClinVar: RCV000019912

In a German male with reticular dysgenesis (267500), Pannicke et al. (2009) identified a homozygous 5,038-bp deletion encompassing parts of exon 6, all of intron 6 and parts of exon 7 reaching into the 3-prime UTR of the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0002   RETICULAR DYSGENESIS

AK2, 1-BP DEL, 118T
SNP: rs387906581, ClinVar: RCV000019913

In a German male with reticular dysgenesis (267500), Pannicke et al. (2009) identified compound heterozygosity for 2 mutations in the AK2 gene: a 1-bp deletion (118delT) leading to a frameshift and premature termination, and a 1A-G transition leading to a met1-to-val (M1V) substitution (103020.0003). The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. Each parent was heterozygous for one of the mutations. The mutations were not found in 112 German or 50 Turkish healthy subjects.


.0003   RETICULAR DYSGENESIS

AK2, MET1VAL
SNP: rs137853206, gnomAD: rs137853206, ClinVar: RCV000019914

For discussion of the met1-to-val (M1V) mutation in the AK2 gene that was found in compound heterozygous state in a patient with reticular dysgenesis (267500) by Pannicke et al. (2009), see 103020.0002.


.0004   RETICULAR DYSGENESIS

AK2, 331, G-A, -1
SNP: rs1192619329, gnomAD: rs1192619329, ClinVar: RCV000019915

In a German male with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a splicing mutation, 331-1G-A, in the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0005   RETICULAR DYSGENESIS

AK2, 1-BP DEL, 453C
SNP: rs1553151177, ClinVar: RCV000019916, RCV002510770

In male and female Turkish sibs with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a 1-bp deletion (453delC) in the AK2 gene, leading to a frameshift and premature termination. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0006   RETICULAR DYSGENESIS

AK2, 498, G-A, +1
SNP: rs777503956, gnomAD: rs777503956, ClinVar: RCV000019917, RCV001778659

In a Turkish female with reticular dysgenesis (267500), the offspring of consanguineous parents, Pannicke et al. (2009) identified homozygosity for a splicing mutation, 498+1G-A, in the AK2 gene. The mutation led to a complete loss of detectable AK2 protein in fibroblasts and in bone marrow mononuclear cells. The parents were heterozygous for the mutation, which was not found in 112 German or 50 Turkish healthy subjects.


.0007   RETICULAR DYSGENESIS

AK2, ASP165GLY
SNP: rs267606643, ClinVar: RCV000019918

In 2 separate pedigrees with reticular dysgenesis (267500), each of whom was consanguineous, Lagresle-Peyrou et al. (2009) identified homozygosity for an A-to-G transition at nucleotide 546 in exon 5 of the AK2 gene, resulting in an asp-to-gly substitution in codon 165 (D165G) within the LID domain. This mutation changed a highly conserved amino acid. The parents were found to be carriers, and unaffected sibs were heterozygous or homozygous for the wildtype allele.


.0008   RETICULAR DYSGENESIS

AK2, LEU183TER
SNP: rs1553150995, ClinVar: RCV000019919

In a female from a consanguineous family affected with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified a 1-bp deletion of C at nucleotide 523 in exon 6 of the AK2 gene (523delC), resulting in a substitution of a termination codon for a leucine at codon 183 (L183X). This mutation was not detected in her sister, and each parent was found to be a carrier.


.0009   RETICULAR DYSGENESIS

AK2, ARG186CYS
SNP: rs267606645, gnomAD: rs267606645, ClinVar: RCV000019920, RCV002281711

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) found compound heterozygosity for mutations in the AK2 gene: a C-to-T transition at nucleotide 556 in exon 6, resulting in an arg-to-cys substitution at codon 186 (R186C), and an exon 2 deletion (see 103020.0010).


.0010   RETICULAR DYSGENESIS

AK2, EX2 DEL
ClinVar: RCV000019921

In a female with reticular dysgenesis (267500) from a nonconsanguineous family, Lagresle-Peyrou et al. (2009) identified compound heterozygosity for deletion of exon 2 of the AK2 gene and an arg186-to-cys substitution (103020.0009). Each parent was a carrier of one of the mutations.


.0011   RETICULAR DYSGENESIS

AK2, ARG103TRP
SNP: rs267606648, gnomAD: rs267606648, ClinVar: RCV000019922

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified a C-to-T transition at nucleotide 307 in exon 3 of the AK2 gene, resulting in an arg-to-trp substitution at codon 103 (R103W). Each of her parents was a carrier for this mutation, which occurs in a highly conserved amino acid residue.


.0012   RETICULAR DYSGENESIS

AK2, LYS233TER
SNP: rs267606646, ClinVar: RCV000019923

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified a 5-kb deletion following nucleotide 633 (633del5kb), resulting in a lys-to-ter substitution at codon 233 (K233X). The patient was homozygous for this mutation. Two of her 3 unaffected sibs, and each of her unaffected parents, were carriers.


.0013   RETICULAR DYSGENESIS

AK2, GLU9TER
SNP: rs267606647, gnomAD: rs267606647, ClinVar: RCV000019924

In a female with reticular dysgenesis (267500), Lagresle-Peyrou et al. (2009) identified homozygosity for a G-to-T transversion at nucleotide 25 in exon 1 of the AK2 gene, resulting in a glu-to-ter codon substitution at amino acid 9 (E9X). The child was homozygous for this mutation. Each of her parents was a carrier.


REFERENCES

  1. Bruns, G. A. P., Regina, V. M. Adenylate kinase-2, a mitochondrial enzyme. Biochem. Genet. 15: 477-486, 1977. [PubMed: 195572] [Full Text: https://doi.org/10.1007/BF00520192]

  2. Carritt, B., King, J., Welch, H. M. Gene order and localization of enzyme loci on the short arm of chromosome 1. Ann. Hum. Genet. 46: 329-335, 1982. [PubMed: 6961883] [Full Text: https://doi.org/10.1111/j.1469-1809.1982.tb01583.x]

  3. Goss, S. J., Harris, H. Gene transfer by means of cell fusion. II. The mapping of 8 loci on human chromosome 1 by statistical analysis of gene assortment in somatic cell hybrids. J. Cell Sci. 25: 39-57, 1977. [PubMed: 561097] [Full Text: https://doi.org/10.1242/jcs.25.1.39]

  4. Kim, H., Lee, H.-J., Oh, Y., Choi, S.-G., Hong, S.-H., Kim, H.-J., Lee, S.-Y., Choi, J.-W., Hwang, D. S., Kim, K.-S., Kim, H.-J., Zhang, J., Youn, H.-J., Noh, D.-Y., Jung, Y.-K. The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth. Nature Commun. 5: 3351, 2014. Note: Electronic Article. [PubMed: 24548998] [Full Text: https://doi.org/10.1038/ncomms4351]

  5. Lagresle-Peyrou, C., Six, E. M., Picard, C., Rieux-Laucat, F., Michel, V., Ditadi, A., Chappedelaine, C. D., Morillon, E., Valensi, F., Simon-Stoos, K. L., Mullikin, J. C., Noroski, L. M., and 10 others. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nature Genet. 41: 106-111, 2009. [PubMed: 19043416] [Full Text: https://doi.org/10.1038/ng.278]

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Contributors:
Bao Lige - updated : 03/27/2019
Ada Hamosh - updated : 1/15/2010
Ada Hamosh - updated : 8/4/2009
Patricia A. Hartz - updated : 10/28/2008
Carol A. Bocchini - updated : 8/6/2003

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
carol : 09/19/2022
carol : 03/28/2019
mgross : 03/27/2019
mcolton : 08/03/2015
terry : 6/11/2012
alopez : 1/26/2010
terry : 1/15/2010
terry : 8/13/2009
carol : 8/12/2009
terry : 8/4/2009
mgross : 10/28/2008
ckniffin : 6/1/2004
tkritzer : 8/8/2003
carol : 8/6/2003
psherman : 4/15/1998
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/26/1989
marie : 3/25/1988
reenie : 2/9/1987
marie : 1/7/1987