BACKGROUND: Acrodysostosis is a rare hereditary disorder described as a primary bone dysplasia with or without hormonal resistance. Pathogenic variants in the PRKAR1A and PDE4D genes are known genetic causes of this condition. The latter gene variants are more frequently identified in patients with midfacial and nasal hypoplasia and neurological involvement. The aim of our study was to analyse and confirm a genetic cause of acrodysostosis in a male patient.
METHODS: We report on a 29-year-old Lithuanian man diagnosed with acrodysostosis type 2. The characteristic phenotype includes specific skeletal abnormalities, facial dysostosis, mild intellectual disability and metabolic syndrome. Using patient\'s DNA extracted from peripheral blood sample, the novel, likely pathogenic, heterozygous de novo variant NM_001104631.2:c.581G > C was identified in the gene PDE4D via Sanger sequencing. This variant causes amino acid change (NP_001098101.1:p.(Arg194Pro)) in the functionally relevant upstream conserved region 1 domain of PDE4D.
CONCLUSIONS: This report further expands the knowledge of the consequences of missense variants in PDE4D that affect the upstream conserved region 1 regulatory domain and indicates that pathogenic variants of the gene PDE4D play an important role in the pathogenesis mechanism of acrodysostosis type 2 without significant hormonal resistance.

Atherosclerosis was an important pathophysiological basis of atherothrombotic stroke, and phosphodiesterase 4D (PDE4D) polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to atherothrombotic stroke. Aim of the present study was to explore the potential association between SNP83 and carotid atherosclerosis (CAS). 204 southern Chinese Han participants were divided into two groups according to the carotid intima-media thickness (IMT) of the carotid artery: CAS group (carotid IMT ≥ 1.0 mm) and non-CAS group (carotid IMT < 1.0 mm). Carotid IMT was measured by color Doppler ultrasound. The PDE4D SNP83 polymorphism was determined by SNaPshot technique. Our study found that SNP83 was associated significantly with CAS susceptibility under the dominant, overdominant and codominant models. After adjusting for age, gender, low-density lipoprotein cholesterol, Hemoglobin A1c, cigarette smoking, hypertension history, and diabetes mellitus history, the association still remained significant (dominant model: crude OR = 2.373, 95% CI: 1.268-4.442, P = 0.007; adjusted OR = 3.129, 95% CI: 1.104-8.866, P = 0.032; overdominant model: crude OR = 1.968, 95% CI: 1.043-3.714, P = 0.037; adjusted OR = 2.854, 95% CI: 1.005-8.108, P = 0.049; codominant: crude OR = 2.102, 95% CI: 1.110-3.979, P = 0.023; adjusted OR = 2.984, 95% CI: 1.047-8.502, P = 0.041). Carotid IMT of carriers with CT + CC genotypes was higher than carriers with TT genotype (P = 0.016). Our results indicated that the SNP83/rs966221 located on PDE4D gene was significantly associated between CAS susceptibility and carotid IMT independently of conventional risk factors in a southern Chinese Han population.

Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes.
The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability.
Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

BACKGROUND: Stroke remains a leading cause of death and disability worldwide. Ischemic stroke (IS) accounts for around 80-85% of total stroke and is a complex polygenic multi-factorial disorder which is affected by a complex combination of vascular, environmental, and genetic factors.
OBJECTIVE: The study was conducted with an aim to examine the relationship of single nucleotide polymorphisms (SNPs) of PDE4D (T83C, C87T, and C45T) gene with increasing risk of IS in patients in North Indian population.
METHODS: In this hospital-based case-control study, 250 IS subjects and 250 age-and sex-matched control subjects were enrolled from the Neurosciences Centre, A.I.I.M.S., New Delhi, India. Deoxyribonucleic acids (DNAs) were extracted using the conventional Phenol-Chloroform isolation method. Different genotypes were determined by Polymerase chain reaction- Restriction fragment length polymorphism method. Odds ratio (OR) and 95% Confidence Interval (CI) of relationship of polymorphisms with risk of IS were calculated by conditional multivariable regression analysis.
RESULTS: High blood pressure, low socioeconomic status, dyslipidemia, diabetes, and family history of stroke were observed to be statistically significant risk factors for IS. Multivariable adjusted analysis demonstrated a statistically significant relationship between SNP 83 of PDE4D gene polymorphism and increasing odds of IS under the dominant model of inheritance (OR, 1.59; 95% CI, 1.02 to 2.50; p value = 0.04) after adjustment of potential confounding variables. Stratified analysis on the basis of TOAST classification demonstrated a statistically significant association for increasing 2.73 times odds for developing large vessel disease stroke as compared to controls (OR, 2.73; 95% CI, 1.16 to 0.02; p value = 0.02). We did not find any significant association of SNPs (C87T and C45T) of the PDE4D gene with the risk of IS.
CONCLUSIONS: SNP 83 of PDE4D gene may increase the risk for developing IS whereas SNP 87 and SNP45 of PDE4D may not be associated with the risk of IS in the North Indian population. Prospective cohort studies are required to corroborate these findings.

In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects, we present a protocol to rank newly designed molecules through the estimation of their IC[Formula: see text] values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC[Formula: see text] values [[Formula: see text](IC[Formula: see text])] and their calculated binding free energies ([Formula: see text]). From 13 known PDE4B inhibitors, we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship; (2) MM-GB/SA post-processing of molecular dynamics (MD) trajectories of the top ranked AutoDock pose improves the linear relationship; (3) by taking into account all representative structures obtained by AutoDock and by averaging MM-GB/SA computations on a series of 40 independent MD trajectories, a linear relationship between [Formula: see text](IC[Formula: see text]) and the lowest [Formula: see text] is achieved with [Formula: see text].

BACKGROUND: The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis.
METHODS: A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I2 > 50%) existed, otherwise the fixed effects model was used.
RESULTS: Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76-0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72-0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64-0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75-1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76-1.00, P = 0.055).
CONCLUSIONS: This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia.

BACKGROUND: Stroke is the second most common cause of death and disability worldwide. It is a multi-factorial disease influenced by both environmental and genetic factors. Studies from the different ethnic regions of world have reported variable results on association of Apolioprotein E (APOE), Methylenetetrahydrofolate reductase (MTHFR), Endothelial Nitric Oxide Synthase (ENOS), Factor V Leiden (F5), Cytochrome P450 4F2 (CYP4F2), beta-fibrinogen and Phosphodiesterase 4D (PDE4D) gene in stroke. There has been substantial evidence from the European descent genetic studies showing that genetic risk of stroke varies as per specific subtypes of ischemic stroke.This study aims to test the hypothesis that above mentioned encoding gene polymorphisms are associated with stroke and to determine whether risk varies as per specific subtypes of stroke.
METHODS: The study design would be case-control study. Six hundred cases with diagnosis of stroke and 600 age and sex matched controls will be recruited. Controls will be matched in 1:1 ratio. Baseline and demographic data will be collected in standardized data collection form. Four ml of blood will be collected in EDTA coated vial and will be used for DNA isolation. Genotyping will be done by using PCR-RFLP method. For the reconfirmation of RFLP results, PCR product of each genotype in triplet for all the selected polymorphism will be sent for DNA sequencing. Data will be analyzed using conditional logistic regression to determine odds ratio associated with the above genes.
CONCLUSIONS: This protocol will assess the association of above mentioned gene polymorphisms with ischemic stroke in North Indian Population. This study will also helpful to determine genetic component of stroke and whether variation in genetic risk as per different subtypes of stroke.

BACKGROUND: The present study aims to assess the association of PDE4D gene polymorphisms (SNP83 and SNP87) with Coronary Heart Disease (CHD) in a single Mendelian population of Delhi.
METHODS: A cross-sectional study was carried out wherein intravenous blood samples were collected from 100 cases and 100 age, sex and ethnicity matched controls along with their demographic, life style, and clinical profiles.
RESULTS: Genotypic frequencies of PDE4D gene variants 83 and 87 did not differ significantly between cases and controls. Odds ratio revealed a 1.4-fold increased risk with PDE4D 83 C allele; though not significant. Both the SNPs showed significant association with serum triglyceride (TG) (P ≤ 0.05). A significant linkage disequilibrium was observed between the SNPs. The haplotype with mutant alleles of the two SNPs showed fivefold increased risk (though not significant) and that with normal allele of SNP 83 and mutant allele of SNP 87 (T-T) was found to be significantly associated with the disease in the present population.
CONCLUSIONS: PDE4D gene variants 83 and 87 did not show any significant association with CHD. However, their interaction with TG and the haplotypic association found in the present population is indicative of the population-specific risk associated with CHD where majority of the individuals have high cholesterol and high Body Mass Index (BMI).

The phosphodiesterase 4B (PDE4B), which is involved in cognitive function in animal models, is a candidate susceptibility gene for schizophrenia (SZ) and bipolar disorder (BP). Variations in PDE4B have previously been associated with SZ, with a suggested gender-specific effect. We have genotyped and analyzed 40 and 72 tagging single nucleotide polymorphisms (tagSNPs) in SZ and BP multicenter samples, respectively, from the Scandinavian Collaboration on Psychiatric Etiology (SCOPE), involving 837 SZ cases and 1,473 controls plus 594 BP cases and 1,421 partly overlapping controls. Six and 16 tagSNPs were nominally associated (0.0005 < or = P < or = 0.05) with SZ and BP, respectively, in the combined samples or in gender-specific subgroups. None of these findings remained significant after correction for multiple testing. However, a number of tagSNPs found to be nominally associated with SZ and BP were located in a high LD region spanning the splice site of PDE4B3, an isoform with altered brain expression in BP patients. Four tagSNPs were associated with SZ in women, but none in men, in agreement with the previously reported gender-specific effect. Proxies of two nominally associated SNPs in the SZ sample were also associated with BP, but the genotypic effect (i.e., homozygosity for the minor allele), pointed in opposite directions. Finally, four SNPs were found to be associated with Positive And Negative Syndrome Scale (PANSS) positive symptom scores in a subgroup of SZ patients (n = 153) or SZ female patients (n = 70). Further studies are needed to evaluate the implicated PDE4B region of interest, for potential involvement in SZ and BP susceptibility.

Sequence variations in genes involved in inflammation system are known to contribute to the risk of cardiovascular diseases (CVD) including stroke. In this study, we performed a genetic association study on the single nucleotide polymorphisms (SNPs) present in the genes CD14 (-159 C/T), TNFalpha (-308 G/A), IL-1alpha (-889 C/T), IL-6 (-174 G/C), PSMA6 (-8 C/G), and PDE4D (SNP83 T/C, respectively) in order to discern their possible role in the susceptibility to stroke in a North Indian population. These SNPs were previously found to be associated with CVD through their contribution to inflammation. A case-control design was used to examine 176 stroke patients (112 ischemic and 64 hemorrhagic stroke patients) and 212 unrelated healthy control individuals. After adjustment for the confounding risk factors, the IL-1alpha -889 T allele carriers (TT+CT) were found to be strongly associated with both forms of stroke (OR=2.56; 95% CI=1.53-4.29; P=0.0004). The CC genotype of PDE4D was found to be associated only with ischemic stroke (OR=2.02; 95% CI=1.08-3.76; P=0.03). None of the variants tested for the CD14, TNFalpha, IL-6, and PSMA6 genes found to confer risk for stroke in the study population. In conclusion, the -889 C/T and SNP83 T/C SNPs of the IL-1alpha and PDE4D genes, respectively, appear to be genetic risk factors for stroke in our study population.