Alternative titles; symbols
HGNC Approved Gene Symbol: PDE4D
Cytogenetic location: 5q11.2-q12.1 Genomic coordinates (GRCh38): 5:58,969,038-60,522,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q11.2-q12.1 | Acrodysostosis 2, with or without hormone resistance | 614613 | Autosomal dominant | 3 |
Cyclic nucleotides are important second messengers that regulate and mediate a number of cellular responses to extracellular signals, such as hormones, light, and neurotransmitters. Cyclic nucleotide phosphodiesterases (PDEs) regulate the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. PDE4D is a class IV cAMP-specific PDE. The PDE4D gene is complex, with at least 9 different variants encoding functional proteins (summary by Milatovich et al. (1994) and Dominiczak and McBride (2003)).
Using degenerate primers based on Drosophila Dnc and rat Dpd to amplify human Dpd orthologs, followed by low-stringency hybridization of a brain cDNA library, Bolger et al. (1993) cloned DPDE3, which they called PDE43, and a partial splice variant, PDE39, that differs in its 5-prime sequence. The deduced DPDE3 protein contains 657 amino acids and has 2 N-terminal domains that share a high degree of conservation with other DPDE proteins, and a C-terminal catalytic domain. RNase protection assays detected DPDE3 transcripts in 5 of 7 cell lines examined.
Using primers designed from rat Pde4d, Nemoz et al. (1996) cloned 2 alternatively spliced variants of PDE4D, which they designated PDE4D2 and PDE4D3, from peripheral blood mononuclear cell mRNA. These variants differed from PDE4D1 primarily in the N-terminal region. In addition, they found that variants PDE4D1 and PDE4D2, but not PDE4D3, lack an upstream conserved region I (UCRI) found in the Drosophila 'dunce' PDE sequence. Western blot analysis of endogenous PDE4D variants in mononuclear cells and of PDE4D2 and PDE4D3 expressed by transfected embryonic kidney cells revealed that PDE4D1, PDE4D2, and PDE4D3 have apparent molecular masses of 72 kD, 67 kD, and 93 kD, respectively.
Bolger et al. (1997) cloned alternative splice variants PDE4D4 and PDE4D5, which encode deduced proteins of 810 and 746 amino acids, respectively. These differ from PDE4D1, PDE4D2, and PDE4D3 in the N-terminal sequence. Transfection of PDE4D4 and PDE4D5 into COS-7 cells resulted in the expression of proteins with apparent molecular masses of 119 kD and 105 kD, respectively.
Miro et al. (2000) identified 3 splice variants that were inactive due to truncation of the C-terminal catalytic domains.
Using common sequences of rat and human PDE4D as probe, Wang et al. (2003) identified PDE4D6 and PDE4D7 in a hippocampal cDNA library. Using primers specific to each isoform, they cloned full-length PCE4D6 and PDE4D7 by PCR of hippocampal cDNA. By searching an EST database for 5-prime alternatively spliced variants, followed by 5-prime RACE and screening a skeletal muscle cDNA library, they cloned PDE4D8. The protein structures of these variants conform to that of other PDE4D isoforms, with a variable N terminus containing UCR1 and UCR2, followed by a C-terminal catalytic core. Sites for secondary modification include several phosphorylation sites, a putative myristoylation site within UCR2, and sites for N-linked glycosylation. PDE4D6 encodes a deduced 518-amino acid protein which lacks the N-terminal UCR1 and half of UCR2 and has a calculated molecular mass of about 59 kD; PDE4D7 encodes a deduced 748-amino acid protein with a calculated molecular mass of about 84.7 kD; and PDE4D8 encodes a deduced 687-amino acid protein. PDE4D7 and PDE4D8 contain both UCR1 and UCR2, which places them in the class of long PDE4D isoforms. Semiquantitative PCR detected PDE4D6 expressed only in brain. PDE4D7 was expressed in several tissues, with stronger expression in lung and kidney, and PDE4D8 was expressed at high levels in heart and skeletal muscle, and more weakly in lung.
Lindstrand et al. (2014) stated that the 2 regulatory domains at the N terminus of the PDE4D protein, UCR1 and UCR2, inhibit activity of the C-terminal catalytic domain and that protein isoforms lacking one or both regulatory domains have a higher activity level.
Bolger et al. (1993) confirmed that PDE43 showed cAMP PDE activity, which was inhibited by several cyclin nucleotide PDE inhibitors.
Nemoz et al. (1996) demonstrated phosphodiesterase activity in embryonic kidney cells following transfection of PDE4D2 and PDE4D3.
Bolger et al. (1997) found that COS cell-expressed and native PDE4D1 and PDE4D2 were localized only in the cytosol, whereas PDE4D3, PDE4D4, and PDE4D5 were expressed in both cytosolic and particulate fractions. Rolipram, a specific PDE4 inhibitor, inhibited all PDE4D isoforms tested, and showed a significantly lower IC50 for the cytosolic forms of PDE4D than for the particulate forms. Bolger et al. (1997) concluded that the N-terminal regions of the various isoforms determine both the subcellular localization and the sensitivity to inhibitors.
Miro et al. (2000) demonstrated that TNFA (191160) upregulated the basal expression of PDE4D in cultured human umbilical vein endothelial cells (HUVEC). Examination of the variants responsive to TNFA revealed that PDE4D4, which was not detected in untreated cells, accumulated beginning 4 hours after treatment and increased at 24 hours. The expression of PDE4D5, transiently induced after 4 hours, was inhibited and became undetectable after 24 hours. The expression of PDE4D1, PDE4D2, and PDE4D3 levels were unchanged.
Using a promoter/reporter assay, Le Jeune et al. (2002) determined that the promoter region for variant PDE4D5, which contains 2 putative cAMP response elements (CREs), was activated in response to increased cellular cAMP. Site-directed mutational analysis revealed that the CRE at position -210 was the principal component underlying the cAMP responsiveness. The authors further determined that cAMP induced PDE4D5 expression in primary cultured human airway smooth muscle cells, leading to upregulated phosphodiesterase activity.
Wang et al. (2003) characterized PDE4D6 and PDE4D7 expressed in insect cells, and showed that both enzymes have a high affinity for cAMP, and both are inhibited by rolipram. The activity of PDE4D7, but not PDE4D6, was elevated in response to protein kinase A (see 176911), presumably through phosphorylation of a PKA site in UCR1.
Dodge-Kafka et al. (2005) identified a cAMP-responsive signaling complex maintained by the muscle-specific A-kinase anchoring protein (AKAP6; 604691) that includes PKA (188830), PDE4D3, and EPAC1 (606057). These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an AKAP6-associated ERK5 (602521) kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits EPAC1, an exchange factor for the small GTPase RAP1 (179520), to enable cAMP-dependent attenuation of ERK5. Pharmacologic and molecular manipulations of the AKAP6 complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, Dodge-Kafka et al. (2005) concluded that 2 coupled cAMP-dependent feedback loops are coordinated within the context of the AKAP6 complex, suggesting that local control of cAMP signaling by AKAP proteins is more intricate than previously appreciated.
McLachlan et al. (2007) found that all 9 PDE4D isoforms were expressed in healthy adult human hippocampus and in hippocampus from a patient with advanced Alzheimer disease (AD; 104300). However, the patient with AD had very low levels of isoforms D3 (25% of controls) and D5 through D9 (0.7 to 7.5%), whereas levels of the short isoform D1 were doubled (262%). Levels of D2 and D4 were essentially unchanged compared to normal.
Using quantitative RT-PCR, Peter et al. (2007) showed that stimulation of CD4-positive T cells increased the expression of PDE4A (600126), PDE4B (600127), and PDE4D in a specific and time-dependent manner. Treatment with small interfering RNA revealed that the different PDE4 subtypes had nonredundant but complementary effects on T-cell cytokine production, with PDE4D having a small but more significant effect than the other PDE4 subtypes on proliferation and IL2 (147680), IL5 (147850), and IFNG (147570) production.
Le Jeune et al. (2002) identified 17 exons of the PDE4D gene spanning just under 1 Mb. They identified 4 putative intronic promoters upstream from the start codons for each of the first 5 isoforms identified. PDE4D1 and PDE4D2 share the same putative promoter which, in the rat sequence, lacks a TATA box, but contains a cAMP-responsive region, a number of GC-rich regions, and binding sites for SP1 (189906), AP1 (see 165160), and AP2 (107580). The promoter for the PDE4D5 variant contains 2 putative CREs and a number of CCAAT enhancer-binding protein-binding sites (see CEBPA, 116897).
Wang et al. (2003) determined that the putative promoter regions of PDE4D6, PDE4D7, and PDE4D8 contain multiple CREs within 2 kb upstream of the starting methionine.
Gretarsdottir et al. (2003) determined that the PDE4D gene contains at least 22 exons and spans about 1.5 Mb.
Milatovich et al. (1994) assigned the PDE4D gene to human chromosome 5 by Southern analysis of somatic cell hybrid lines and regionalized the assignment to 5q12 by fluorescence in situ hybridization (FISH). The homologous locus was assigned to mouse chromosome 13 by Southern analysis of recombinant inbred (RI) mouse strains.
Szpirer et al. (1995) mapped the PDE4D gene to human chromosome 5 and to rat chromosome 2 using somatic cell hybrids segregating either human or rat chromosomes, respectively.
Susceptibility to Ischemic Stroke
Gretarsdottir et al. (2002) mapped susceptibility to stroke to chromosome 5q12; see STRK1 (606799). Gretarsdottir et al. (2003) reported fine mapping of the locus and testing it for association with stroke. They found the strongest association in the PDE4D gene, especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis (ischemic stroke). They observed a substantial dysregulation of multiple PDE4D isoforms in affected individuals. Notably, they found that haplotypes could be classified into 3 distinct groups: wildtype, at-risk, and protective. The at-risk haplotype had significantly lower expression of the PDE4D7 and PDE4D9 isoforms. They proposed that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathologic process underlying ischemic stroke.
Rosand et al. (2006) noted that 9 studies had been published as follow-up to the report of Gretarsdottir et al. (2002): 5 had claimed replication of the findings and 4 had not. A total of 11 SNPs in the PDE4D gene had been investigated among different phenotypic groups of stroke patients, such as small-vessel, large-vessel, cardioembolic, and all ischemic. Using haplotype data to examine the correlation between these various SNPs, Rosand et al. (2006) found that none of the SNPs was significantly correlated to the at-risk haplotype identified by Gretarsdottir et al. (2002). The authors concluded that the original PDE4D association with stroke should be viewed with caution.
Acrodysostosis 2 with or without Hormone Resistance
In 4 unrelated patients with acrodysostosis-2 (ACRDYS2; 614613), Michot et al. (2012) identified 4 different de novo heterozygous missense mutations in the PDE4D gene (600129.0001-600129.0004). The first 2 mutations were identified by exome sequencing and confirmed by Sanger sequencing. Although all 4 missense mutations were predicted to be pathogenic by PolyPhen and were absent from 200 controls, functional studies were not performed. The patients ranged in age from 3 to 7 years. All had advanced bone age, facial dysostosis with nasal hypoplasia and depressed nasal bridge, severe brachydactyly with short metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses. All also had intellectual disability with speech and psychomotor retardation. One had intrauterine growth retardation, but none had short stature. None had evidence of hormone resistance, except 1 who had increased parathyroid hormone (PTH). Two patients developed intracranial hypertension due to sinus thrombosis. Michot et al. (2012) concluded that the mutations resulted in decreased phosphodiesterase activity, a dysregulation in cAMP levels, and alterations in the cAMP signaling pathway, resulting in the growth and intellectual deficits in these patients.
Independently and simultaneously, Lee et al. (2012) identified de novo heterozygous missense mutations in the PDE4D gene (600129.0005-600129.0007) in 3 unrelated patients with ACRDYS2. The mutations were predicted to be pathogenic and were absent from almost 6,000 exomes, but no functional studies were performed. However, because PDE4D is a dimer, the missense alleles may cause the phenotype via a dominant-negative effect on the protein. All 3 patients had small hands and midface hypoplasia, 2 had mild short stature, and 2 had lumbar stenosis. One had normal psychomotor development, 1 had significantly impaired development, and the third had mild developmental disability. One had congenital hypothyroidism, 1 had cryptorchidism, and 1 had no endocrine abnormalities.
In 3 sibs with ACRDYS2, Lynch et al. (2013) identified a heterozygous mutation in the PDE4D gene (A243V; 600129.0008). Their father, who also carried the mutation, was found to have subtle clinical abnormalities consistent with the disorder. Four additional unrelated patients with a similar phenotype were each found to carry a de novo heterozygous missense mutation in the PDE4D gene. The data confirmed that PDE4D is a major locus for acrodysostosis, as different mutations were identified in all 5 probands in the series.
Lindstrand et al. (2014) identified 5 different de novo heterozygous missense mutations in the PDE4D gene (see, e.g., 600129.0009 and 600129.0010) in 5 unrelated patients with acrodysostosis-2 who did not carry PRKAR1A (188830) mutations. Three PDE4D mutations were found by exome sequencing, whereas 2 were found by Sanger sequencing. Four of the mutations occurred in the UCR1 or UCR2 regulatory regions of the protein; the fifth occurred in the catalytic domain. Overexpression of 16 PDE4D point mutations in zebrafish embryos resulted in consistent developmental abnormalities, including short curved body, fragile tail, microcephaly, heart edema, cyclopia, and an enlarged protruding jaw. The percentage and severity of embryos with specific defects varied from 9 to 41%. These findings indicated that missense point mutations causing acrodysostosis are pathogenic.
PDE4D is the mammalian homolog of 'dunce' in Drosophila. Flies deficient in this PDE display impairments of the central nervous system and reproductive functions (Dudai et al., 1976). Although only 1 dunce PDE has been described in the fly, 4 orthologous genes are present in mice, rats, and humans: PDE4A, PDE4B, PDE4C (600128), and PDE4D. The encoded proteins share considerable homology in their catalytic and regulatory domains. To examine the role of a PDE in cAMP signaling in vivo, Jin et al. (1999) inactivated the PDE4D gene in mice. This isozyme is involved in feedback regulation of cAMP levels. Mice deficient in PDE4D exhibited delayed growth as well as reduced viability and female fertility. The decrease in fertility of the null female was caused by impaired ovulation and diminished sensitivity of the granulosa cells to gonadotropins. These pleiotropic phenotypes demonstrated that PDE4D plays a critical role in cAMP signaling and that the activity of this isoenzyme is required for the regulation of growth and fertility.
Muscarinic cholinergic signaling plays an essential role in the control of normal airway functions and in the development of pulmonary disease states, including asthma. Hansen et al. (2000) demonstrated that the airways of mice deficient in the cAMP-specific phosphodiesterase PDE4D were no longer responsive to cholinergic stimulation. Airway hyperreactivity that followed exposure to antigen was also abolished in PDE4D -/- mice, despite apparently normal lung inflammatory infiltration. The loss of cholinergic responsiveness was specific to the airway, not observed in the heart, and was associated with a loss of signaling through muscarinic receptors with an inability to decrease cAMP accumulation. These findings demonstrated that the PDE4D gene plays an essential role in cAMP homeostasis and cholinergic stimulation of the airway, and in the development of hyperreactivity. In view of the therapeutic potentials of PDE4 inhibitors, the findings provided the rationale for novel strategies that target a single PDE isoenzyme.
Lindstrand et al. (2014) found that morpholino-based suppression of the pde4d ortholog in zebrafish embryos resulted in developmental defects, including shortened body length, curved tail, large head, and heart edema.
In a 7-year-old boy with acrodysostosis-2 with hormone resistance (ACRDYS2; 614613), Michot et al. (2012) identified a de novo heterozygous 673C-A transversion in the PDE4D gene, resulting in a pro225-to-thr (P225T) substitution in a conserved residue. The mutation was identified by exome sequencing and confirmed by Sanger sequencing; it was not found in 200 controls. The patient had intrauterine growth retardation, advanced bone age, facial dysostosis with nasal hypoplasia and depressed nasal bridge, severe brachydactyly with short metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses. Laboratory studies showed increased PTH, but no other signs of hormone resistance. He had impaired intellectual development with speech delay, as well as impairment of fine motor skills. He also developed intracranial hypertension with sinus thrombosis.
In a 4-year-old boy with acrodysostosis-2 without hormone resistance (ACRDYS2; 614613), Michot et al. (2012) identified a de novo heterozygous 677T-C transition in the PDE4D gene, resulting in a phe226-to-ser (F226S) substitution in a conserved residue. The mutation was identified by exome sequencing and confirmed by Sanger sequencing; it was not found in 200 controls. The patient had advanced bone age, facial dysostosis with nasal hypoplasia and depressed nasal bridge, severe brachydactyly with short metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses. He did not have signs of hormone resistance. He had intellectual disability with speech delay, as well as impairment of fine motor skills.
In a 4-year-old boy with acrodysostosis-2 without hormone resistance (ACRDYS2; 614613), Michot et al. (2012) identified a de novo heterozygous 568T-G transversion in the PDE4D gene, resulting in a ser190-to-ala (S190A) substitution. He had advanced bone age, facial dysostosis with nasal hypoplasia, depressed nasal bridge, and prominent mandible, severe brachydactyly with short metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses. He did not have signs of hormone resistance. He had intellectual disability with speech and psychomotor retardation, as well as intracranial hypertension with thrombophlebitis.
In a 3-year-old boy with acrodysostosis-2 wihout hormone resistance (ACRDYS2; 614613), Michot et al. (2012) identified a de novo heterozygous 1759A-C transversion in the PDE4D gene, resulting in a thr587-to-pro (T587P) substitution in a conserved catalytic domain that confers the phosphodiesterase activity. The patient had advanced bone age, facial dysostosis with nasal hypoplasia and depressed nasal bridge, severe brachydactyly with short metacarpals, metatarsals, and phalanges, and cone-shaped epiphyses. He did not have signs of hormone resistance. He also had impaired intellectual development with speech and psychomotor retardation.
In a girl with acrodysostosis-2 without hormone resistance (ACRDYS2; 614613), Lee et al. (2012) identified a de novo heterozygous 682C-G transversion in the PDE4D gene, resulting in a gln228-to-glu (Q228E) substitution in a conserved residue in the amino-terminal UCR1 domain present in the longer isoform. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient had small hands and midface hypoplasia, but did not have short stature or developmental delay. There were no endocrine abnormalities.
In a boy with acrodysostosis-2 without hormone resistance (ACRDYS2; 614613), Lee et al. (2012) identified a de novo heterozygous 1769A-C transversion in the PDE4D gene, resulting in a glu590-to-ala (E590A) substitution in a conserved residue in the catalytic domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient had previously been reported by Graham et al. (2001) (case R1). He had intrauterine growth retardation, mild short stature, small hands and feet, midface hypoplasia, maxillonasal hypoplasia, and significantly delayed development. Other features included lumbar stenosis and cryptorchidism, but other endocrine abnormalities were not present.
In a boy with acrodysostosis-2 with hormone resistance (ACRDYS2; 614613), Lee et al. (2012) identified a de novo heterozygous 2018G-A transition in the PDE4D gene, resulting in a gly673-to-asp (G673D) substitution in a conserved residue in the catalytic domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient had previously been reported by Graham et al. (2001) (case 2). At age 4 years, he was referred for developmental delay, speech delay, dysmorphic facial features, and brachydactyly. He had acrodysostosis with brachydactyly, cone-shaped epiphyses, and lumbar stenosis. He also had congenital hypothyroidism, which resolved by age 3 years.
In 3 sibs with acrodysostosis-2 without hormone resistance (ACRDYS2; 614613), Lynch et al. (2013) identified a heterozygous 728C-T transition in the PDE4D gene, resulting in an ala243-to-val (A243V) substitution at a highly conserved residue in the upstream conserved region (UCR). The patients had typical features of the disorder, including round face, nasal hypoplasia, flattened nasal bridge, brachydactyly, speech delay, and intellectual deficits. Two also developed obesity. None had endocrine abnormalities. The father, who was found to carry the mutation, was observed retrospectively to have subtle features of the disorder, including learning disabilities, shortened metacarpals, and variable brachydactyly.
In a 14.7-year-old boy with acrodysostosis-2 with hormone resistance (ACRDYS2; 614613), Lindstrand et al. (2014) identified a de novo heterozygous c.677T-G transversion in exon 3 of the PDE4D gene, resulting in a phe226-to-cys (F226C) substitution in the UCR1 domain. The patient had short stature, maxillary hypoplasia, short nose with bulbous tip, red hair, blue eyes, small hands and feet, and brachydactyly. He also had speech delay and intellectual disability. Laboratory studies showed mild parathyroid hormone resistance and type 1 diabetes mellitus. Overexpression of mutant mRNA into zebrafish embryos caused developmental defects, including short curved body with fragile tail, microcephaly, heart edema, cyclopia, and a protruding jaw in 20% of embryos. Lindstrand et al. (2014) postulated that the mutation caused a loss of function in the regulatory region, resulting in increased PDE activity and decreased cellular cAMP with a dominant-negative effect.
In a 3.5-year-old girl with acrodysostosis-2 (ACRDYS2; 614613), Lindstrand et al. (2014) identified a de novo heterozygous c.2033T-C transition in exon 15 of the PDE4D gene, resulting in an ile678-to-thr (I678T) substitution in the catalytic domain. The patient had nasal and maxillary hypoplasia, bulbous nasal tip, epicanthal folds, low-set ears, blond hair and blue eyes, short fingers and arms, and small hands and feet. She had delayed psychomotor development with speech delay. Overexpression of mutant mRNA into zebrafish embryos caused developmental defects, including short curved body with fragile tail, microcephaly, heart edema, cyclopia, and a protruding jaw in 35% of embryos. Endocrine abnormalities were observed. Lindstrand et al. (2014) postulated that the mutation caused a gain of catalytic activity, resulting in increased PDE activity and decreased cellular cAMP with a dominant-negative effect.
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