A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.

We report that a single-nucleotide polymorphism (SNP) in the gene (PTPN22) encoding the lymphoid protein tyrosine phosphatase (LYP), a suppressor of T-cell activation, is associated with type 1 diabetes mellitus (T1D). The variants encoded by the two alleles, 1858C and 1858T, differ in a crucial amino acid residue involved in association of LYP with the negative regulatory kinase Csk. Unlike the variant encoded by the more common allele 1858C, the variant associated with T1D does not bind Csk.

Lack of evidence for association between D2S124 and D2S111 polymorphisms of the SCN2A gene and idiopathic generalized epilepsy with generalized tonic clonic seizures.

Idiopathic generalized epilepsy syndromes are generally considered as brain channelopathies due to alteration of several genes. The aim of our study was to compare the distribution of D2S124 and D2S111 genetic polymorphisms of the SCN2A gene between cases with a specific idiopathic generalized epilepsy subtype (with generalized tonic-clonic seizures) and healthy controls. Allele frequencies of both the D2S111 and the D2S124 polymorphisms were not significantly different between cases and control. Further studies are needed to investigate if possible polymorphic variants of SCN2A gene may influence seizures susceptibility of idiopathic generalized epilepsy with tonic-clonic seizures.

Association between D18S474 locus on chromosome 18q12 and idiopathic generalized epilepsy.

Idiopathic generalized epilepsy is one of the most common forms of epilepsy. The aetiology of IGE is genetically determined, but the pattern of inheritance is still undefined. Recent studies in common IGE showed evidence for linkage on chromosome 18q12 at the D18S474 locus. The aim of our study was to compare the distribution of allelic variants of D18S474 locus in children affected by generalized tonic-clonic seizures and in healthy controls. We studied 295 children: 121 cases and 174 controls. We found that the D18S474(8) allele was significantly more frequent and D18S474(9) significantly less frequent in cases compared with controls (p<.001). In conclusions, our findings show the association between the D18S474 marker and IGE in which early onset GTCS represent the most prevalent seizure type.

Serum glucose concentration and ACP1 genotype in healthy adult subjects.

Acid phosphatase locus 1 (ACP 1 ) or cytosolic low molecular weight protein tyrosine phosphatase is a polymorphic enzyme that can hydrolyze phosphotyrosine-containing peptides of the human insulin receptor and of band 3 protein. High-activity ACP 1 may favor an increase in serum glucose concentration through a depression of insulin action and through inactivation of aldolase, phosphofructokinase, and glyceraldehyde-3-phosphate dehydrogenase induced by dephosphorylation of band 3 protein. In diabetic subjects, we have previously reported lower serum glucose concentration in subjects with low-activity ACP 1 A and AB phenotypes. We have now studied the relationship between serum glucose concentration and ACP 1 genotype in a sample of 137 healthy adult workers of our university. In males, serum glucose concentration is significantly higher in medium-high- than in low-activity ACP 1 genotypes. With advancing age in males, there is a progressive increase in glycemic differential between medium-high- and low-activity ACP 1 genotypes. The data suggest that normal variability of ACP 1 genotype influences serum glucose concentration in normal individuals. Such influence depends on sex and in males becomes more marked with advancing age.

Lack of association between IDE genetic variability and Down's syndrome.

Virtually all patients with Down's syndrome develop Alzheimer disease (AD) during their life; thus, it is extremely important to investigate potential determinants of AD in this population. Previous studies found an association of DS with -48C/T presenilin-1 and with the -850 tumor necrosis factor-alpha, two polymorphisms of genes involved in amyloid beta modulation In this study, we evaluated whether the insulin-degrading enzyme (IDE), a protease involved in the degradation of endogenous brain-derived Abeta peptides, is involved in DS-related AD. To this end, 287 DS patients were compared with 251 apparently healthy controls, in order to assess the association between DS and two single nucleotide polymorphisms located on the introns 14 and 24 of the IDE gene. The comparison of allele and genotype distribution between cases and controls showed no evidence for an association with regard to IDE polymorphism, for both the SNPs (i.e., IDE 185 and IDE 199). In conclusion, the findings of our study suggest that the two IDE polymorphisms considered in the analysis do not appear to play a major role in DS-related AD.

The role of -850 tumor necrosis factor-alpha and apolipoprotein E genetic polymorphism in patients with Down's syndrome-related dementia.

Down's syndrome (DS) is a disease with a complex etiology. It is likely that other factors besides genes located on chromosome 21 may play a role in clinical features of affected patients. Tumor necrosis factor-alpha (TNF-alpha) (6p21.3) and apolipoprotein E (APOE) (19q13.2) are candidate genes as they interact with the brain deposition of Abeta, one of the neuropathological hallmarks in DS. We examined 136 DS patients and 113 controls for -850 TNF-alpha and APOE polymorphisms. The -850T frequency in DS was significantly higher than in controls (P<0.005, OR 2.05, 95% CI 1.22-3.49) while the APOE E4 allele was negatively selected in patients compared to normal subjects (P<0.005, OR 0.38, 95% CI 0.20-0.71). Our findings suggest that the -850T allele, which is more common among patients at high risk of dementia such as those with DS, might eventually play a role in the development of dementia; no inference on the role of the allele APOE E4 in DS-related dementia may be derived from our results.

Association between presenilin-1 -48C/T polymorphism and Down's syndrome.

Individuals with Down's syndrome (DS), i.e., trisomy 21, over 40 years of age, are likely to develop neuropathological changes characteristic of Alzheimer's disease (AD). The involvement of chromosome 21 both in DS and AD suggests a shared genetic susceptibility to these disorders, but genetic determinants are still undefined. The -48C/T polymorphism in the PSEN1 promoter is a possible candidate, since it has recently been associated with an increased risk of early onset AD. Based on the assumption that the excess of dementia in DS might be a consequence of a different distribution of the -48C/T polymorphism, we investigated the association between DS and this polymorphism in patients with trisomy 21 and controls. Overall, 260 DS patients and 197 controls were recruited at the Department of Neurosciences, Tor Vergata University of Rome. Cases and controls had similar age and gender distribution. High molecular weight DNA was extracted from whole blood samples collected in EDTANa(2) and -48C/T genotypes were determined. Genotype and allele frequencies were compared between cases and controls. Cases were less likely than controls to have the CC genotype ( P = 0.05). A significant difference for allele distribution between DS cases and controls was found, with DS showing a lower frequency of the allele C compared with the control population (OR: 0.57; 95% CI: 0.35-0.91; P = 0.01). No significant interaction of PSEN1 with age, gender, ApoE and -850 TNF-alpha polymorphisms was found. The association found suggests that the -48C/T polymorphism in the PSN1 gene promoter, which is involved in the modulation of amyloid beta load in human AD, is associated with DS. However, the biological role of this polymorphism in DS-related dementia remains unclear and merits further investigation.

Convulsive disorder and the genetics of signal transduction; a study of a low molecular weight protein tyrosine phosphatase in a pediatric sample.

Recent studies point to an involvement of kinases and phosphatases in ionic channel regulation and in physiopathologic mechanisms leading to convulsive disorders. Acid phosphatase locus 1 (ACP1), also named cytosolic low molecular weight phosphotyrosine phosphatase, is a highly polymorphic phosphatase that is especially abundant in the central nervous system and is known to be involved in several signal transduction pathways. We studied ACP1 in 122 children with idiopathic generalized tonic-clonic seizures, 80 children with febrile convulsions, and 417 controls from the population of Rome. Low activity phenotypes of ACP1 (*A/*A and *A/*B) were found to be over-represented while high activity phenotypes (*C/*C and *B/*C) were under-represented in generalized seizures cases compared to controls (P < 0.005). No significant difference was observed between febrile convulsion cases and controls. These observations suggest a protective role of the high activity ACP1 phenotypes against seizures in children.

Association of the ACP1 genotype with metabolic parameters upon initial diagnosis of type 1 diabetes.

BACKGROUND: ACP1, also called cLMWPTP (cytosolic Low Molecular Weight PTPase) is a highly polymorphic enzyme involved in the modulation of signal transduction by insulin, PDGF receptors, and T-cell receptors. The enzyme is controlled by a locus on chromosome 2, with three common codominant alleles; the corresponding six genotypes show strong variations in total enzymatic activity. The purpose of our research was to determine the relationship of ACP1 with glycemic level, ketoacidosis and HbA1C in children with Type 1 diabetes. MATERIAL/METHODS: We studied 189 consecutive children with Type 1 diabetes, from the Pediatric Clinic of Sassari University. The ACP1 genotype was determined by PCR and digestion by specific restriction enzymes. RESULTS: At initial diagnosis a strong negative correlation was observed between glycemic level and ACP1 activity, with the highest levels in genotypes with low activity. Ketoacidosis and HbA1C show a similar pattern of relationship with ACP1. A comparative analysis of the data on Type 1 diabetes with previously obtained data on Type 2 diabetes shows an opposite pattern of relationship between ACP1 and metabolic parameters. Moreover, correlation between glycemia and HbA1C in Type 1 diabetes is much weaker than in Type 2 diabetes. CONCLUSIONS: These differences suggest that the enzyme might be involved in different signal transduction pathways relevant in the pathogenesis of these two classes of diabetic disorders. It would be interesting to study the possible correlation in Type 1 diabetes between ACP1 and immunological parameters.