We here describe a leukemogenic role of the homeobox gene
, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of
in a leukemia patient harboring a ...t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases a total of 23 positive patients out of 62 (37.1%), and in 6 of 75 (8%) of AML cell lines.
is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney.
expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas.
-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as
and
, was revealed. Similar results were obtained in
-transduced CD34
cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that
expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type
We also observed that
expression significantly associates with an increased frequency of acute promyelocytic leukemia with
and AML with t(8;21)(q22;q22.1);
classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of
, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic ...deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue‐ and temporal‐specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent‐of‐origin effect.
Synopsis
Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.
Two rare variants of maternal origin (an intragenic deletion and a missense change) were identified in CADPS2 in a cohort of patients with neurodevelopmental abnormalities; the p. Asp1113Asn variant was shown to disrupt the interaction with dopamine receptor type 2 (D2DR).
Differentially methylated sites were identified in CADPS2 first intron, in blood and amygdala, but they did not show a parent‐of‐origin methylation pattern typical of an imprinted gene.
Tissue‐specific, monoallelic maternal expression of CADPS2 in blood and in the amygdala plays a key role in regulating social interactions and supports the importance of a fine modulation of CADPS2 for human behavior.
CADPS2 variants may contribute to intellectual disability and autism susceptibility, and their role should be interpreted in light of possible parent‐of‐origin effect.
Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver ...transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATP-dependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel mis-sense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVE
We describe a maturity-onset diabetes of the young (MODY) case with mutations involving both HNF4A and HNF1A genes.
RESEARCH DESIGN AND METHODS
A male patient was diagnosed with diabetes at ...age 17; the metabolic control rapidly worsened to insulin requirement. At that time no relatives were known to be affected by diabetes, which was diagnosed years later in both the parents (father at age 50 years, mother at age 54 years) and the sister (at age 32 years, during pregnancy).
RESULTS
The genetic screening showed a double heterozygosity for the mutation p.E508K in the HNF1A/MODY3 gene and the novel variant p.R80Q in the HNF4A/MODY1 gene. The genetic testing of the family showed that the father carried the MODY3 mutation while the mother, the sister, and her two children carried the MODY1 mutation.
CONCLUSIONS
MODY1 and MODY3 mutations may interact by chance to give a more severe form of diabetes (younger age at presentation and early need of insulin therapy to control hyperglycemia).
Docosahexaenoic acid (DHA) is a major constituent of neuronal and retinal membranes and plays a crucial role in brain and visual development within the first months of life. Dietary intakes are ...fundamental to provide neonates with adequate DHA supply; hence, maternal supplementation might represent a useful strategy to implement DHA contents in breast milk (BM), with possible benefits on neonatal neurodevelopment.
is a small crustacean rich in highly available phospholipid-bound DHA. This pilot study aimed to evaluate whether maternal supplementation with krill oil during breastfeeding increases long-chain polyunsaturated fatty acids (LCPUFAs) BM contents.
Mothers of infants admitted to the Neonatal Intensive Care Unit were enrolled in this open, randomized-controlled study between 4 and 6 weeks after delivery and randomly allocated in 2 groups. Group 1 received an oral krill oil-based supplement providing 250 mg/day of DHA and 70 mg/day of eicosapentaenoic acid (EPA) for 30 days; group 2 served as control. BM samples from both groups were collected at baseline (T0) and day 30 (T1) and underwent a qualitative analysis of LCPUFAs composition by gas chromatography/mass spectrometry.
Sixteen breastfeeding women were included. Of these, 8 received krill-oil supplementation and 8 were randomized to the control group. Baseline percentage values of DHA (%DHA), arachidonic acid (%AA), and EPA (%EPA) did not differ between groups. A significant increase in %DHA (T0: median 0.23% IQR 0.19;0.38, T1:0.42% 0.32;0.49,
0.012) and %EPA (T0: median 0.10% IQR 0.04;0.11, T1:0.11% 0.04;0.15,
0.036) and a significant reduction in %AA (T0: median 0.48% IQR 0.42;0.75, T1:0.43% 0.38;0.61,
0.017) between T0 and T1 occurred in Group 1, whereas no difference was seen in Group 2. Consistently, a significant between-group difference was observed in percentage changes from baseline of DHA (Δ%DHA, group 1: median 64.2% IQR 27.5;134.6, group 2: -7.8% -12.1;-3.13,
0.025) and EPA (Δ%EPA, group 1: median 39% IQR 15.7;73.4; group 2: -25.62% -32.7;-3.4,
0.035).
Oral krill oil supplementation effectively increases DHA and EPA contents in BM. Potential benefits of this strategy on brain and visual development in breastfed preterm neonates deserve further evaluation in targeted studies.
: www.ClinicalTrials.gov, identifier NCT03583502.
The outcome of patients underwent to allogeneic stem cell transplantation (allo- SCT) is closely related to graft versus host disease (GvHD) and graft versus leukemia (GvL) effects which can be ...mediated by mHAgs. 23 mHAgs have been identified and reported to be differently correlated with GVHD or GVL and the aim of this work was develop a method to genotype the mHAgs described so far. For this study we used MALDI-TOF iPLEX Gold Mass Array technology. We tested 46 donor/recipient matched pairs that underwent allo-SCT because of Philadelphia positive (Ph+) chronic myeloid leukemia (n = 29) or Ph+ acute lymphoblastic leukemia (n =17). Our data show that sibling pairs had a lesser number of mHAgs mismatches compared to MUD pairs. Notably, donor/recipient genomic mismatch on DPH1 was correlated with an increased risk of acute GvHD and LB-ADIR-1R mismatch on graft versus host direction was correlated with a better RFS with no increase of GvHD risk. Our work provides a simple, accurate and highly automatable method for mHAgs genotyping and suggest the role of mHAgs in addressing the immune reaction between donor and host.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Little is known about the impact of space (geography/ancestry) and time (age of the individuals) on DNA methylation variability in humans. We investigated DNA methylation of the imprinted IGF2/H19 ...locus in: i) a cohort of individuals homogeneous for age and gender (males with restricted age range: 30-50 years) belonging to four Italian districts representative of the major genetic clines, informative for the geographical dimension; ii) a cohort of monozygotic (MZ) and dizygotic (DZ) twins of different ages (age-range: 22-97 years), informative for the temporal dimension. DNA methylation of the analyzed regions displayed high levels of inter-individual variability that could not be ascribed to any geographical cline. In MZ twins we identified two IGF2/H19 regions where the intra-couple variations significantly increased after the age of 60 years. The analysis of twins' individual life histories suggests that the within twin pairs difference is likely the result of the aging process itself, as sharing a common environment for long periods had no effect on DNA methylation divergence. On the whole, the data here reported suggest that: i) aging more than population genetics is responsible for the inter-individual variability in DNA methylation patterns in humans; ii) DNA methylation variability appears to be highly region-specific.
Gene polymorphisms involved in homocysteine-methionine pathway result in hyperhomocysteinemia, a predisposing condition to several diseases. Methylenetetrahydrofolate reductase (MTHFR) is a key ...enzyme in folate and homocysteine metabolism. The two known functional polymorphisms of
MTHFR
gene, 677C>T and 1298A>C have been implicated in a variety of multifactorial diseases: cardio-cerebrovascular and neurodegenerative disorders, autoimmune diseases, birth defects, diabetes, neuropsychiatric disorders, cancer and renal disease. C667T, and to a lesser extent A1298C polymorphisms, have been also reported to have a pharmacogenetic role in predicting drug toxicity in cancer and rheumatoid arthritis treatment. We review here the principal effects of the
MTHFR
gene variations in different clinical conditions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Genetic and pharmacological inactivation of cannabinoid CB1 receptors (CB1Rs) exacerbates disease course in experimental autoimmune encephalomyelitis, suggesting that CB1Rs might play a ...role in the neurodegenerative damage associated with multiple sclerosis (MS).
Objectives: To see whether CNR1 gene polymorphism could influence disease progression in relapsing–remitting MS.
Methods: The genotype of 350 patients for the number of AAT repeats was characterized and correlation studies were performed with measures of disease severity and progression.
Results: MS patients with the homozygous genotype for long AAT repeats in the CNR1 gene had more severe disease and higher risk of progression. These subjects had significantly higher scores on both the progression index and the MS severity scale. Furthermore, the percentage of patients with MS functional composite score progression or Bayesian Risk Estimate for MS (BREMS) score ≥2 (considered at very high risk of secondary progression) was significantly higher in the AAT long group than in the short group, while the frequency of patients with BREMS score ≤−0.63 (very likely to remain progression-free) was not significantly different between the two groups, although lower in the long group. Finally, the frequency of patients prescribed a second-line treatment was significantly higher among subjects of the AAT long group, providing a further, indirect indication of higher disease severity.
Conclusions: The results of the present investigation point to CB1R as an important modulator of disease severity in relapsing MS subjects.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
AIM: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts. METHODS: Human ...leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type i and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls. RESULTS: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs48%, P= 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%,P= 0.01) and in controls (16% vs34%, P= 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 I talian AIH patients than controls (17% vs 35%, P= 0.01). CONCLUSION: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and the yare less frequent than in North American patients. B8DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.
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