CD33 and SIGLECL1 Immunoglobulin Superfamily Involved in Dementia

Abstract

<jats:title>Abstract</jats:title> <jats:p>Sialic acid-binding immunoglobulin-type lectins, which are predominantly expressed in immune cells, represent a family of immunomodulatory receptors with inhibitory and activating signals, in both healthy and disease states. Genetic factors are important in all forms of dementia, especially in early onset dementia. CD33 was recently recognized as a genetic risk factor for Alzheimer disease (AD). Here, we present a 2-generation family with 4 members, the father and the 3 siblings, characterized by an early form of unusual dementia exhibiting a behavioral variant close to behavioral variant frontotemporal dementia phenotype and severe forms of memory loss suggestive of AD. We analyzed the CD33 gene in this family and identified 10 single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block associated with the disease. We also identified a tag SNP, rs2455069-A&amp;gt;G, in CD33 exon 2 that could be involved with dementia risk. Additionally, we excluded the presence of C9orf72 expansion mutations and other mutations previously associated with sporadic FTD and AD. The tag SNP association was also analyzed in selected sporadic AD patients from the same Southern Italy region. We demonstrate that CD33 and SIGLECL1 have a significantly increased level of expression in these patients.</jats:p>

CD33 rs2455069 SNP: Correlation with Alzheimer’s Disease and Hypothesis of Functional Role

“…Based on the evidence of the possible involvement in an unusual form of dementia of the SNP rs2455069-A>G in exon 2 of CD33 gene [ 29 ], leading to a change from arginine to glycine in position 69, we widened the analysis of this SNP to a cohort of AD patients from southern Italy. We found that the genotype frequency for the rs2455069 polymorphism in the control group was 11.1% ( n = 15) for the GG, 53.0% ( n = 77) for the AG, and 31.8% ( n = 43) for the AA genotypes.…”

“…The high-resolution melting analysis (HRM) was performed as previously described [ 29 ] on a LightCycler 480 Instrument II (Roche, Basel, Switzerland) and analyzed using LightCycler ® 480 Gene Scanning Software 1.5.1. High-resolution melting Mastermix (Roche) was used.…”

“…Specific primers used for amplification and sequencing by the Sanger method and the electropherograms were analyzed with Chromas 2.22 software and aligned according to reference sequences present in GenBank ( ; accessed on 1 September 2019). Templates were amplified in 96-well plates and ~30 ng analyzed in a 20 µL final volume reaction as previously specified [ 29 ].…”

“…We recently identified the SNP rs2455069 in exon 2 of the human CD33 gene on chromosome 19, which is involved in an unusual familial form of dementia [ 29 ]. This SNP has been previously identified in a block of eight correlated SNPs in CD33 significantly associated with cognitive decline in univariate analysis in the all-female cohort, with highly significant effects on hyaluronan synthase-1 (HAS1) expression in the temporal cortex [ 30 ].…”

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men

“…The genes MARVELD2 and MGMT were also identified in the single CpG site analyses. The increased expression of gene SIGLECL1 , which is located in chr19: 51774377–51774667, has been found in patients with dementia (54). The three CpGs (i.e., cg14724749, cg14884932, cg15497724) are mapped to either the island or N shore area of gene SIGLECL1 , and their methylation levels were all negatively (although not statistically) associated with optimism level in the single CpG site analyses (data not shown).…”