Genetic basis of neurodevelopmental disorders in 103 Jordanian families

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.     

Novel association suggests multiple independent QTLs within chromosome 5q21-33 region control variation in total humans IgE levels

Asthma is a common, heterogeneous, complex disease accompanied by raised total and specific immunoglobulin-E (IgE) antibody levels. Despite numerous previous reports of linkage and association of asthma, atopy and serum IgE levels to genes within the 5q21-33 region, definitive, replicable results are still not available. We used the classical twin design to (i) estimate the relative contributions of genes and environment to variation in total IgE levels, (ii) assess genetic linkage, and (iii) examine allelic association of 11 microsatellite markers spanning the 5q21-33 region to total IgE. Variation in total IgE level was shown to be highly heritable (65%). Although evidence for linkage of the 11 microsatellites to IgE was not observed, the omnibus test of association, not confounded by population substructure, showed positive association of D5S393 and D5S673 to IgE. Genes in the vicinity of D5S673 include hepatitis A virus receptor (HAVCR-1) and IL-12B. Recently, the mouse orthologue of HAVCR-1, the T-cell membrane family of proteins, have been shown to be in strong association with expression of airway hyperactivity in a mouse model of human asthma and atopy. IL-12B subserves many proinflammatory functions and also induces B cells proliferation.     

Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions

It has been shown that the functions and the rescue from apoptosis by proinflammatory mediators of polymorphonuclear leukocytes (PMN) tend to diminish with aging. Here, we investigated the role of protein tyrosine phosphatases (PTP), especially Src homology domain-containing protein tyrosine phosphatase-1 (SHP-1), in the age-related, altered PMN functions under granulocyte macrophage-colony stimulating factor (GM-CSF) stimulation. The inhibition of PTP suggested a differential effect of GM-CSF on phosphatase activity in modulating PMN functions with aging. The down-regulation of phosphatase activity of immunopurified SHP-1 from lipid rafts of PMN of young donors was found significantly altered at 1 min of stimulation with aging. In young donors, SHP-1 is displaced from lipid rafts at 1 min of stimulation, whereas in the elderly, SHP-1 is constantly present. We assessed in PMN lipid rafts the phosphorylation of tyrosine and serine residues of SHP-1, which regulates its activity. We observed an alteration in the phosphorylation of tyrosine and serine residues of SHP-1 in PMN of elderly subjects, suggesting that GM-CSF was unable to inhibit SHP-1 activity by serine phosphorylation. GM-CSF activates Lyn rapidly, and we found alterations in its activation and translocation to the lipid rafts with aging. We also demonstrate that SHP-1 in the PMN of elderly is constantly recruited to Lyn, which cannot be relieved by GM-CSF. In contrast, in the young, the resting recruitment could be relieved by GM-CSF. Our results suggest an alteration of the SHP-1 modulation by GM-CSF in lipid rafts of PMN with aging. These alterations could contribute to the decreased GM-CSF effects on PMN.     

Comparison of hormonal changes of estrous cycle with cytology of cervical mucosa and hematological parameters in dairy heifers

Cervical mucosa cytology and hematological parameters in heifers were determined during different phases of the estrous cycle. Ten healthy Holstein heifers were synchronized by two injections of PGF_2α at 14 days interval. Blood and cervical mucosa samples were collected at days of 0, 2, 10 and 19 of estrous cycle. Differential cell counts were performed, and the progesterone level was measured by radioimmunoassay. Progesterone levels in diestrus and the percentages of neutrophils in metestrus were shown to be higher than in other phases of the estrous cycle (P<0.05). In contrast, the percentages of epithelial cells in metestrus were lower than other phases (P<0.05). A difference was also seen (P<0.05) in blood progesterone levels between four estrous cycle phases. However, there was no significant difference in RBCs, hemoglobin, hematocrit, WBCs, neutrophils, lymphocytes, monocytes, and eosinophils between four estrous cycle phases. Hormonal changes in different phases of estrous cycle affect neutrophil presence in cervical mucosa. It is important to consider cervical cytology and hormonal assay together for evaluation of dairy cow reproductive tract function.     

Obesity is Associated with Genetic Variants That Alter Dopamine Availability

Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI ≥ 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals ( MAOA: χ²= 15.45, p = 0.004; MAOB: χ²= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the 'at risk genotype' - low activity genotypes at both the MAOA and MAOB loci - shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets.     

Prevalence of coagulase-positive staphylococci in the skin of dogs; antibacterial resistance and plasmid profile of the isolates

This study was designed to understand the prevalence of coagulase-positive staphylococci in the skin of dogs and the role of dogs as reservoirs of pathogenic and antimicrobial-resistant staphylococci. Swab samples were taken from the surface of the skin at muzzle sites of 100 clinically normal dogs. Antibiotic susceptibility of coagulase-positive staphylococci isolates was assessed by antibiotic disc diffusion method using filter paper discs and plasmid DNAs were extracted from the isolates. Staphylococci were isolated from 79 of the 100 dogs sampled and of these 51 were coagulase positive. All coagulase-positive staphylococci isolates were resistant to penicillin G, amoxicillin, cefazolin, streptomycin, erythromycin, ampicillin, tetracycline, gentamicin, trimethoprim-sulfamethoxazole, and enrofloxacine at 100%, 100%, 72%, 48%, 44%, 44%, 12%, 4%, 8%, and 4% respectively. Characterization of plasmid DNAs by agarose gel electrophoresis showed that 22 out of the 51 coagulase-positive staphylococci isolates harbored a single plasmid. The results of the present study indicate that pathogenic and resistant staphylococci are located in the skin of the dogs and may transfer to human and other hosts. It is important to establish reliable antibiotic sensitivity data regarding these bacteria to select suitable antibacterial treatment.