Alternative titles; symbols
HGNC Approved Gene Symbol: ADCY5
Cytogenetic location: 3q21.1 Genomic coordinates (GRCh38): 3:123,282,296-123,449,090 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.1 | Dyskinesia with orofacial involvement, autosomal dominant | 606703 | Autosomal dominant | 3 |
| Dyskinesia with orofacial involvement, autosomal recessive | 619647 | Autosomal recessive | 3 | |
| Neurodevelopmental disorder with hyperkinetic movements and dyskinesia | 619651 | Autosomal recessive | 3 |
ADCY5 belongs to the adenylate cyclase (EC 4.6.1.1) family of enzymes responsible for the synthesis of cAMP (Ludwig and Seuwen, 2002).
By database analysis and PCR of a human cDNA library, Ludwig and Seuwen (2002) cloned full-length ADCY5. EST database analysis revealed 2 alternative polyadenylation sites. The deduced protein contains 1,261 amino acids. Semiquantitative RT-PCR detected high expression of ADCY5 in heart and testis, moderate expression in brain, prostate, ovary, small intestine, and colon, and low expression in lung and liver.
Mencacci et al. (2015) found expression of the ADCY5 gene in multiple human brain regions, with highest expression in the putamen and adult striatum. ADCY5 expression progressively increased in the striatum during embryonic development.
Ludwig and Seuwen (2002) determined that the ADCY5 gene contains 21 exons and spans 167 kb. The first exon is 95 kb upstream of the clustered next 20 exons.
By Southern blot analysis of somatic cell hybrid DNAs, Gaudin et al. (1994) mapped the ADCY5 gene to chromosome 3. Using isotopic in situ hybridization, Haber et al. (1994) mapped the ADCY5 gene to 3q13.2-q21. By fluorescence in situ hybridization, Edelhoff et al. (1995) mapped the ADCY5 gene to human chromosome 3q13 and to mouse chromosome 16 in the B5 region. In both species, the gene maps close to GAP43 (162060).
Stumpf (2021) mapped the ADCY5 gene to chromosome 3q21.1 based on an alignment of the ADCY5 sequence (GenBank AF497517) with the genomic sequence (GRCh38).
Autosomal Dominant Dyskinesia with Orofacial Involvement
In affected members of a large German family with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Chen et al. (2012) identified a heterozygous missense mutation in the ADCY5 gene (A726T; 600293.0001). The family had previously been reported by Bird and Hall (1978). Chen et al. (2015) identified this same heterozygous mutation in a large American family with the disorder; the family had previously been reported by Bird et al. (1976) and Fernandez et al. (2001). In vitro functional expression studies performed by Chen et al. (2014) showed that mutant A726T ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function.
In 2 unrelated teenaged girls of European ancestry with DSKOD, Chen et al. (2014) identified a de novo heterozygous mutation in the ADCY5 gene (R418W; 600293.0002). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that both mutant A726T and R418W ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function. One of the girls with a more severe phenotype also carried a de novo heterozygous N1882S variant in the DOCK3 gene (603123), which may have a role in neuronal activity and could have possibly contributed to the phenotype. In addition, sequence reads suggested that the girl with the less severe phenotype may have been somatic mosaic for the R418W mutation. Chen et al. (2014) postulated that these findings may have played a role in the phenotypic variability observed in the 2 patients.
In a French father and son with DSKOD, Carapito et al. (2015) identified a heterozygous splice site mutation in the ADCY5 gene (600293.0003). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells had decreased ADCY5 mRNA levels, consistent with degradation of the mutant transcript, a loss of function, and haploinsufficiency. The patients had an early onset hyperkinetic movement disorder with dystonia and chorea, but no facial myokymia, thus expanding the phenotype. The findings also suggested that haploinsufficiency of ADCY5 is pathogenic, although a gain-of-function effect could not be excluded.
In a 14-year-old boy (L-3482) adopted from Southeastern Europe with DSKOD, Westenberger et al. (2017) identified a heterozygous missense mutation in the ADCY5 gene (D1015E; 600293.0004). The mutation, which was found by direct sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. In addition to a hyperkinetic movement disorder, the patient had paroxysmal limb weakness reminiscent of alternating hemiplegia of childhood. The report further expanded the phenotype associated with ADCY5 mutations.
In a 21-year-old woman with DSKOD, Dean et al. (2019) identified a de novo heterozygous missense mutation in the ADCY5 gene (Y233H; 600293.0005) affecting a conserved residue in the M1 domain. The mutation, which was found by whole-genome sequencing, was not present in the ExAC or 1000 Genomes Project databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be likely pathogenic according to ACMG criteria. In addition to dyskinesia and dystonia, the patient had spastic paraplegia and mild distal sensory impairment. Dean et al. (2019) noted that a heterozygous missense variant (E908K) identified by Waalkens et al. (2018) in a patient with spastic paraparesis and mild dystonia affected the M2 domain.
In an 18-year-old man (INDF10_3) of Indian origin with DSKOD, Kumar et al. (2019) identified a de novo heterozygous missense mutation in the ADCY5 gene (M1029K; 600293.0006). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing and filtered against control databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic according to ACMG criteria. The patient had myoclonic dystonia, congenital encephalopathy, and daily paroxysmal ballismus.
Autosomal Recessive Dyskinesia with Orofacial Involvement
In 2 sibs with autosomal recessive dyskinesia with orofacial involvement (DSKOR; 619647), Barrett et al. (2017) identified compound heterozygous mutations in the ADCY5 gene (600293.0007 and 600293.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The parents, who were heterozygous carriers of 1 of the mutations, were clinically unaffected.
In 6 sibs, born of consanguineous Arab parents, with DSKOR, Bohlega et al. (2019) identified a homozygous missense mutation in the ADCY5 gene (D588N; 600293.0009). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The parents, who were heterozygous carriers of the mutation, were clinically unaffected.
Neurodevelopmental Disorder with Hyperkinetic Movements and Dyskinesia
In 2 sibs, born of unrelated Japanese parents, with neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD; 619651), Okamoto et al. (2021) identified a homozygous missense mutation affecting the C terminus of the ADCY5 gene (R1238W; 600293.0010). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. At 3 and 1.5 years of age, the patients had severe intellectual disability, axial hypotonia with inability to control the heard, poor eye contact, and dystonic posturing. The parents, who were heterozygous carriers of the mutation, were clinically unaffected.
In 3 sibs, born of consanguineous Egyptian parents, with NEDHYD, Kaiyrzhanov et al. (2021) identified a homozygous splice site mutation in the ADCY5 gene (600293.0011). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro minigene constructs confirmed that the mutation resulted in splicing defects of ADCY5. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. The patients had a severe form of the disorder with poor overall growth, various involuntary movements, severe intellectual disability, and inability to walk or talk. One had cardiomyopathy and died at 4.5 years of age. The carrier parents were clinically unaffected.
Associations Pending Confirmation
For discussion of a possible association between variation in the ADCY5 gene and fasting plasma glucose, birth weight, and 2-hour plasma glucose levels as quantitative traits, see 613460.
Kim et al. (2006) found that Adcy5-null mice had decreased behavioral responses to morphine, including locomotor activation, analgesia, tolerance, reward, physical dependence, and withdrawal symptoms, compared to wildtype mice. Adcy5-null mice also showed attenuated responses to selective mu (600018) and delta (165195) opioid receptor agonists, whereas responses to kappa (165196) opioid receptor agonists were similar to wildtype mice. The results indicated that ADCY5 is an important component of mu- and delta-opioid receptor signal transduction mechanisms in the striatum and provided further support for the importance of the cAMP pathway as a mediator of opioid action.
In affected members of a large multigenerational German family with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), previously reported by Bird and Hall (1978) and Fernandez et al. (2001), Chen et al. (2012) identified a heterozygous c.2176G-A transition in exon 10 of the ADCY5 gene, resulting in an ala726-to-thr (A726T) substitution at a highly conserved residue between the first intracellular cyclase homology domain and the second membrane-spanning domain. The mutation was identified by exome sequencing of 1 affected individual and was not found in 3,510 control exomes. Chen et al. (2012) noted that Adcy5-null mice develop a movement disorder that is worsened by stress (Kim et al., 2006), supporting the pathogenicity of the A726T mutation.
In vitro functional expression studies performed by Chen et al. (2014) showed that mutant A726T ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function.
In affected members of a large 5-generation family (EHC) with DSKOD, previously reported by Bird et al. (1976) and Fernandez et al. (2001), Chen et al. (2015) identified a heterozygous A726T mutation in the ADCY5 gene. The mutation, which was found by direct Sanger sequencing, segregated completely with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Haplotype analysis showed that the German family reported by Chen et al. (2012) and family EHC, from the US, did not share a common haplotype; the mutations arose independently. The EHC family had originally been diagnosed with benign hereditary chorea (see 118700). Chen et al. (2015) noted that the A726T mutation is associated with a relatively mild phenotype. Fernandez et al. (2001) stated that the phenotype in this family was nonprogressive in adulthood and that dementia was not observed, although some patients had educational or behavioral difficulties, possibly resulting from social isolation.
In 2 unrelated teenaged girls of European ancestry with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Chen et al. (2014) identified a de novo heterozygous c.1252C-T transition in the ADCY5 gene, resulting in an arg418-to-trp (R418W) substitution at a conserved residue in the sixth helical segment of the first transmembrane domain. The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that mutant R418W ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function.
In 2 unrelated patients of UK and Pakistani ancestry with DSKOD, Mencacci et al. (2015) identified a heterozygous R418W mutation. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In the first family, the mutation was inherited from the patient's mildly affected father who was somatic mosaic for the mutation. R418W occurred de novo in the proband from family 2. Functional studies of the variant were not performed. The probands had typical features of the disorder with onset of progressive and severe choreodystonic dyskinesias with orofacial involvement in the first years of life. The hyperkinetic movements were exacerbated by action, excitement, stress, and fatigue.
Shetty et al. (2020) reported an Indian man with DKSOD who had the R418W mutation (c.1252C-T, NM_183357.2) in mosaic state with low mutant read depth. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was absent in the parents. The patient had paroxysmal involuntary movements during sleep.
In a French father and son with autosomal dominant dyskinesia with facial involvement (DSKOD; 606703), Carapito et al. (2015) identified a heterozygous G-to-A transition (c.2088+1G-A) in intron 8 of the ADCY5 gene, resulting in a splicing defect. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells had decreased ADCY5 mRNA levels, consistent with degradation of the mutant transcript, a loss of function, and haploinsufficiency. The patients had an early-onset hyperkinetic movement disorder with dystonia and chorea, but no facial myokymia, thus expanding the phenotype. The findings also suggested that haploinsufficiency of ADCY5 is pathogenic, although the authors could not rule out a gain-of-function effect via production of a long alternatively spliced mRNA.
Meneret et al. (2019) reported an 11-year-old boy with DSKOD who was mosaic for the c.2088+1G-A mutation. These authors postulated a gain-of-function effect, although no functional studies of the variant or studies of patient cells were performed. The patient had a remarkable favorable response to caffeinated coffee, which resulted in near complete resolution of the dyskinetic episodes. Meneret et al. (2019) postulated that the caffeine antagonized adenosine A2A receptors, which would inhibit the ADCY5 enzyme.
In a 14-year-old boy (L-3482) adopted from Southeastern Europe with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Westenberger et al. (2017) identified a heterozygous c.3045C-A transition in the ADCY5 gene, resulting in an asp1015-to-glu (D1015E) substitution at a conserved residue in the second cytoplasmic domain that forms the catalytic pocket. The mutation, which was found by direct sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. In addition to a hyperkinetic movement disorder, the patient had paroxysmal limb weakness reminiscent of alternating hemiplegia of childhood. The report further expanded the phenotype associated with ADCY5 mutations.
In a 21-year-old woman with hyperkinetic movement disorder with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Dean et al. (2019) identified a de novo heterozygous c.697T-C transition in exon 1 of in the ADCY5 gene, resulting in a tyr233-to-his (Y233H) substitution at a conserved residue in the M1 domain. The mutation, which was found by whole-genome sequencing, was not present in the ExAC or 1000 Genomes Project databases. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to be likely pathogenic according to ACMG criteria. In addition to dyskinesia and dystonia, the patient had spastic paraplegia and mild distal sensory impairment, further expanding the phenotype.
In an 18-year-old man (INDF10_3) of Indian origin with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Kumar et al. (2019) identified a de novo heterozygous c.3086T-A transversion (c.3086T-A, NM_183357.2) in exon 18 of the ADCY5 gene, resulting in a met1029-to-lys (M1029K) substitution. The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing and filtered against control databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic according to ACMG criteria. The patient had myoclonic dystonia, congenital encephalopathy, and daily paroxysmal ballismus.
In 2 sibs with autosomal recessive dyskinesia with orofacial involvement (DSKOR; 619647), Barrett et al. (2017) identified compound heterozygous mutations in the ADCY5 gene: a c.3037C-T transition (c.3037C-T, NM_183357), resulting in an arg1013-to-cys (R1013C) substitution at a conserved residue, and a 20-bp deletion (c.409_428del20; 600293.0008), predicted to result in a frameshift and premature termination (Gly137CysfsTer184). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. R1013C was not present in the ExAC database. Functional studies of the variants and studies of patient cells were not performed. The parents, who were each a heterozygous carrier of 1 of the mutations, were clinically unaffected.
For discussion of the 20-bp deletion (c.409_428del20, NM_183357) in the ADCY5 gene, predicted to result in a frameshift and premature termination (Gly137CysfsTer184), that was found in compound heterozygous state in 2 sibs with autosomal recessive dyskinesia with orofacial involvement (DSKOR; 619647) by Barrett et al. (2017), see 600293.0007.
In 6 sibs, born of consanguineous Arab parents, with 2 sibs with autosomal recessive dyskinesia with orofacial involvement (DSKOR; 619647), Bohlega et al. (2019) identified a homozygous c.1762G-A transition in exon 6 of the ADCY5 gene, resulting in an asp588-to-asn (D588N) substitution at a highly conserved residue. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The parents, who were heterozygous carriers of the mutation, were clinically unaffected.
In 2 sibs, born of unrelated Japanese parents, with neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD; 619651), Okamoto et al. (2021) identified a homozygous c.3712C-T transition (c.3712C-T, NM_183357.2) in exon 21 of the ADCY5 gene, resulting in an arg1238-to-trp (R1238W) substitution at a highly conserved residue in the C terminus. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant was not present in public databases. Functional studies of the variant and studies of patient cells were not performed. At 3 and 1.5 years of age, the patients had severe intellectual disability, axial hypotonia with inability to control the heard, poor eye contact, and dystonic posturing. The parents, who were heterozygous carriers of the mutation, were clinically unaffected.
In 3 sibs, born of consanguineous Egyptian parents, with neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD; 619651), Kaiyrzhanov et al. (2021) identified a homozygous G-to-T transversion (c.897+1G-T, NM_001199642.1) in intron 7 of the ADCY5 gene, predicted to result in a splicing defect. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro minigene constructs confirmed that the mutation resulted in splicing defects of ADCY5. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. The patients had a severe form of the disorder with poor overall growth, various involuntary movements, severe intellectual disability, and inability to walk or talk. One had cardiomyopathy and died at 4.5 years of age. The carrier parents were clinically unaffected.
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