Carmelo Romano

The CC genotype of transforming growth factor-β1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression

Transforming growth factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against β-amyloid-induced neurodegeneration. Recently, a specific impairment of the TGF-β1 signaling pathway has been demonstrated in Alzheimers disease (AD) brain. TGF-β1 is also involved in the pathogenesis of depressive disorders, which may occur in 30-40% of AD patients. The TGF-β1 gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T/C) and +25 (G/C), which are known to influence the level of expression of TGF-β1. We investigated TGF-β1 +10 (T/C) and +25 (G/C) SNPs and allele frequencies in 131 sporadic AD patients and in 135 healthy age- and sex-matched controls. Genotypes of the TGF-β1 SNPs at codon +10 (T/C) and +25 (G/C) did not differ between AD patients and controls, whereas the allele frequencies of codon +10 polymorphism showed a significant difference (P = 0.0306). We also found a different distribution of the +10 (C/C) phenotype (continuity-corrected χ(2) test with one degree of freedom = 4.460, P = 0.0347) between late onset AD (LOAD) patients and controls (P = 0.0126), but not between early onset AD (EOAD) patients and controls. In addition, the presence of the C/C genotype increased the risk of LOAD regardless of the status of apolipoprotein E4 (odds ratio [OR] = 2.34; 95% CI = 1.19-4.59). Compared to patients bearing the T/T and C/T polymorphisms, LOAD TGF-β1 C/C carriers also showed > 5-fold risk to develop depressive symptoms independently of a history of depression (OR = 5.50; 95% CI = 1.33-22.69). An association was also found between the TGF-β1 C/C genotype and the severity of depressive symptoms (HAM-D(17) ≥ 14) (P < 0.05). These results suggest that the CC genotype of the TGF-β1 gene increases the risk to develop LOAD and is also associated with depressive symptoms in AD.

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation

Given that Alzheimers pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need.

DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome

STUDY QUESTION Are DNMT3B promoter polymorphisms among maternal risk factors for the birth of a child with Down syndrome (DS)? SUMMARY ANSWER Present results suggest that combinations of functional DNMT3B promoter polymorphisms might modulate maternal risk of birth of a child with DS. WHAT IS KNOWN ALREADY The DNMT3B gene codes for DNA methyltransferase 3b (DNMT3b), a protein required for genome-wide de novo methylation, for the establishment of DNA methylation patterns during development and for regulating the histone code and DNA methylation at centromeric regions. Two common functional DNMT3B promoter polymorphisms, namely -149 C > T (rs2424913) and -579 G > T (rs1569686), have been extensively investigated in cancer genetic association studies but less is known about their role in non-cancer diseases. Early in 1999, it was supposed that impaired DNA methylation of pericentromeric regions might represent a maternal risk factor for having a baby with DS. STUDY DESIGN, SIZE AND DURATION We aimed to investigate DNMT3B -149 C > T and -579 G > T polymorphisms as maternal risk factors for the birth of a child with DS. The study was performed on DNA samples from 172 mothers of DS individuals (135 aged <35 years when they conceived) and 157 age-matched mothers of unaffected individuals. PARTICIPANTS/MATERIALS, SETTING AND METHODS Genotyping was performed by means of the PCR-RFLP technique. MAIN RESULTS AND THE ROLE OF CHANCE The DNMT3B -579T allele [odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.48-0.94, P = 0.02], the DNMT3B -579 GT genotype (OR = 0.55; 95% CI = 0.35-0.87 , P = 0.01) and the combined DNMT3B -579 GT + TT genotype (OR = 0.55; 95% CI = 0.36-0.86 , P = 0.008) were associated with reduced risk of birth of a child with DS. A joint effect of the two polymorphisms was observed and the combined -579 GT/-149 CC genotype resulted in decreased DS risk (OR = 0.22; 95% CI = 0.08-0.64, P = 0.003). The effect remained statistically significant after Bonferronis correction for multiple comparisons. Similar results were obtained when the analysis was restricted to women who conceived a DS child before 35 years of age. LIMITATIONS AND REASONS FOR CAUTION To the best of our knowledge, this is the first genetic association study aimed at evaluating DNMT3B polymorphisms as maternal risk factors for DS. Replication of the findings in other populations is required. WIDER IMPLICATIONS OF THE FINDINGS If confirmed in subsequent studies, DNMT3B promoter polymorphisms might be additional markers to be taken into account when evaluating the contribution of one-carbon (folate) metabolism to the maternal risk of birth of a child with DS.

Gene expression profiling and qRT-PCR expression of RRP1B, PCNT, KIF21A and ADRB2 in leucocytes of Down’s syndrome subjects

1Laboratory of Cytogenetics, Oasi Institute for Research on Mental Retardation and Brain Aging, Troina 94018, Italy 2Unit of Pediatrics and Medical Genetics, Oasi Institute for Research on Mental Retardation and Brain Aging, Troina 94018, Italy 3Genopolis Consortium for Functional Genomics, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan 20126, Italy 4Singapore Immunology Network (SIgN), 8A Biomedical Grove, Singapore 138648, Singapore 5UO Psichiatria, AOU Vittorio Emanuele-Policlinico, Department of Clinical and Molecular Biomedicine, University of Catania, Catania 95100, Italy 6Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano 20133, Italy

SPANX-B and SPANX-C (Xq27 region) gene dosage analysis in Sicilian patients with melanoma.

The incidence of melanoma has dramatically increased in many countries (it is 4.5 cases every 100 000 inhabitants in Sicily) and Xq27 region contains genes important in cancer like the SPANX (sperm protein associated with the nucleus in the X chromosome) gene family. These genes, made up of two exons separated by an intron of about 650 base pair, are expressed in sperm cells and in many tumours, including melanoma. These observations suggested that SPANX genes, or some of them, may be involved in melanoma development. The aim of this study was to investigate the genetic variability of SPANX-B and SPANX-C in a sample of Sicilian male population including patients with melanoma of the skin and controls. A total of 99 patients were enrolled in this study. They included: 17 male patients with cutaneous melanoma and 82 normal males. Semiquantitative fluorescent multiplex PCR dosage analysis was carried out to identify the variety of classes of SPANX-B and SPANX-C genes. Sixteen and 13 genetic classes were detected for SPANX-B and SPANX-C genes, respectively. A statistical significant difference for a particular class of SPANX-C gene was found comparing patients with melanoma and controls (P=0.011). Further investigations should be conducted to confirm these observations and to evaluate the possible implication of other genes of the region Xq27–28 in melanoma.

SPAG5 mRNA is over-expressed in peripheral blood leukocytes of patients with Down’s syndrome and cryptorchidism

Men with Down’s syndrome (DS) have an increased risk of cryptorchidism, but the mechanisms causing its onset are not clear. Cryptorchidism causes a primary testiculopathy responsible for infertility. SPAG5 mRNA is predominantly expressed in testis in pachytene spermatocytes. This observation prompted us to evaluate the expression of SPAG5 gene in five DS men with cryptorchidism and five normal healthy men (controls) by quantitative real-time PCR in peripheral blood leukocytes. We found that SPAG5 is over expressed in the five men with DS and cryptorchidism compared with five age- and sex-matched normal controls. This finding suggests that the increased expression of this gene may play a pathogenic role durin testicular development in subjects with DS and cryptorchidism.

Differential expression of PARP1 mRNA in leucocytes of patients with Down's syndrome

Down’s syndrome (DS) is one of the most common numer-ical chromosomal aberrations, usually caused by trisomy ofchromosome 21, and is the most frequent genetic cause ofmental retardation. People with DS can develop some traitsof Alzheimer disease at an earlier age than subjects with-out trisomy 21 (Wisniewski

PARP1 and CASP3 gene expression in a patient with multiple head and neck squamous cell carcinoma and Parkinson disease

Dear Sir,This letter describes an interesting case of a 98-year-oldwoman with multiple head and neck squamous cell carci-noma (HNSCC) and Parkinson disease (PD). The followingsquamous cell cancers were discovered in this patient: (1)squamous cell carcinoma of the tongue, diagnosed andexcised in 2004 with complete clinical recovery; and (2) insitu squamous cell carcinoma of the right cheek and theneck, diagnosed in 2009. She also presented difficulty inthe dexterity of the right hand and a typical PD asymmetricpresentation. Indeed, the patient had a rest tremor andcogwheel rigidity, bradykinesia bilaterally, stooped pos-ture, turns en bloc, and decreased armswing on the right.These symptoms were responsive to the administration of

Expression of LDOC1 mRNA in leucocytes of patients with Down’s syndrome

Down’s syndrome (DS), or trisomy 21, results from an extra chromosome 21 which is due to failure of normal chromosomal segregation during meiosis. Individuals with trisomy 21 can develop premature ageing and some traits of Alzheimer disease at an earlier age than subjects without trisomy 21 (Wisniewski et al. 1985). These individuals were thought to experience a neurodegenerative process because of the presence of an extra copy of the amyloid precursor protein (APP) gene located on chromosome 21, but this hypothesis has not been entirely confirmed by the literature (Elsayed and Elsayed 2009; Arriagada et al. 2010). Several studies have amply demonstrated that genes related to apoptosis play a crucial role in neurodegenerative diseases, indeed apoptotic pathways appear to play a causal role in neurodegenerative processes and in cancer proliferation (Engidawork and Lubec 2001; Gulesserian et al. 2001; Seidl et al. 2001; Yoo et al. 2001; Engidawork and Lubec 2001; Fromage and Anglade 2002; Lubec and Engidawork 2002). The cancer process is favoured when the apoptotic surveillance is, for any reason (Hu and Kavanagh 2003), decreased; conversely, when the apoptotic process is some what encouraged, neurodegenerative processes, such as those related to Alzheimer disease, will be prevailing (Elmore 2007). The leucine zipper, downregulated in cancer 1 (LDOC1) gene, was mapped on chromosome X at q27 and consists of only one exon (OMIM 300402). The Xq27 region is

Poly (ADP-ribose) polymerase-1 (PARP-1) -410C/T polymorphism in Sicilian patients with Parkinson's disease.

Parkinsons disease (PD) is one of themost common neurodegenerative disorders. PD is a chronic and progressive neurologic disorder characterized by the presence of intracytoplasmic inclusions, named Lewy bodies (LB), and by the degeneration of dopaminergic neurons in the substantia nigra. Most PD cases are sporadic, but about 15% of them are associatedwith genetic causes [1]. Apoptosis is a programmed cell death process under both normal physiological and pathological conditions,moreover, has been indicated as one of the importantmechanisms leading to the death of dopaminergic neurons in the substantia nigra of PD patients [2]. In vitro culture studies, on animal models, and human studies on postmortem brains from PD patients have demonstrated the role of apoptosis in PD [3]. Poly (ADP-ribose) polymerase1 (PARP-1), is a nuclearmultifunctional enzyme involved in the cellular activity of oxidative stress; oxygen radicals damageDNA strands and activate PARP-1 that repairs DNA, but excessive PARP-1 activation leads to cell death by energy depletion [4]. Furthermore, PARP-1 is required for translocation of the apoptosis-inducing factor (AIF) from themitochondria to the nucleus [5] and it is proteolytically cleaved at the onset of apoptosis by CASP3 [6]. Infante et al. (2007) [7] studied the polymorphism (−410 C/T; rs2793378) in the promoter region of PARP-1 gene, in PD patients and controls and a protective effect against PD was found for heterozygosity −410 C/T. In the present study, we evaluated the −410 C/T promoter variant of PARP-1gene by sequence analysis in Sicilian patients with PD and in normal controls. A total of 264 subjects, including 136 PD patients (58women and 78 men, mean 76.3 ± 7.4 years) and 128 control subjects (64 women and 64 men, mean 73.6 ± 8.5 years), were recruited at the Oasi Institute of Troina (Italy). PDpatientswere diagnosed according to standard criteria [8]. The control subjects were individuals without symptoms of PD and/ or family history of PD.Written informed consent was obtained from all the participants or from their families. This study was approved by the ethical committee of the Oasi Institute. Patients and controls were all born in Sicily. DNA was isolated from a lymphocyte-enriched fraction of whole blood with NUCLEON BACC3 for extraction of genomic DNA kit (Amersham Pharmacia Biotech, Milan, Italy) using amodified protocol of Salemi et al. [9]. PCR reactions contained 1 μM of the following promoter primers: PARP-1 forward, 5-TCC AGT GGC ACT ATC AT-3, and PARP-1 reverse, 5-GTT GTG AGA CAT AGG CCG AAT C-3, 0.2 mM