Analysis of candidate genes for macular telangiectasia type 2

Purpose: To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach.Methods: Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they cosegregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts.Results: We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism.Conclusions: We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel

Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Objective Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. Methods We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. Results In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03–4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Interpretation Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies

Untangling the Manganese-α-synuclein Web

Neurodegenerative diseases affect a significant portion of the aging population. Several lines of evidence suggest a positive association between environmental exposures, which are common and cumulative in a lifetime, and development of neurodegenerative diseases. Environmental or occupational exposure to manganese (Mn) has been implicated in neurodegeneration due to its ability to induce mitochondrial dysfunction, oxidative stress and α-synuclein (α-Syn) aggregation. The role of the α-Syn protein vis-a-vis Mn is controversial, as it seemingly plays a duplicitous role in neuroprotection and neurodegeneration. α-Syn has low affinity for Mn, however an indirect interaction cannot be ruled out. In this review we will examine the current knowledge surrounding the interaction of α-Syn and Mn in neurodegenerative process

Four families with multiple relatives affected with MacTel.

<p>Black shaded symbols represent affected; dark gray shading represents possibly affected; light gray shading represents probably not affected; unshaded symbols represent unaffected or unexamined relatives. Numbered individuals were enrolled and examined.</p

LOD, HLOD, and NPL scores for chromosome 1 in 17 families.

<p>The 1-LOD support interval around the maximum LOD of 3.45 is shaded in gray.</p

Segregating haplotypes and IBD allele sharing.

<p>Putative risk haplotypes (shown in red and designated with a star) are shown for two families where the parents in both families were genotyped and the phased haplotypes were resolved. Allele sharing identical by descent is shown for six additional families (five ASPs and one affected sibling trio). Phased haplotypes were not resolved in families where parental genotypes were missing. Regions with one allele shared IBD are shown in dark blue; regions with two alleles shared IBD are shown in purple.</p

NPL scores indicating IBD allele sharing on chromosome 1 in 8 families.

<p>Recombinations were mapped by determining IBD allele sharing in 8 families. Regions where at least one allele is shared IBD are marked in green; regions excluded by virtue of no alleles shared IBD are marked in red. Gray bars represent the 1-LOD support interval. For ASPs with parental genotypes missing, 0.3 = 2 alleles shared, 0 = 1 allele shared, −0.3 = 0 alleles shared. For ASPs with parents genotyped and one parent affected, 0.3 = 2 alleles shared, 0.12 = 1 allele shared from the affected parent, −0.12 = 1 allele shared from the unaffected parent, −0.3 = 0 alleles shared. For the affected sib trio, 0.6 = 2 alleles shared between all sibs, 0.3 = 1 allele shared between all sibs, and −.12 = 0 alleles shared between all sibs.</p

Genome-wide affected only linkage scan in 17 families with 71 individuals.

<p>Colored bars at the bottom of the figure label each chromosome. A maximum LOD of 3.45 score was observed at chromosome 1q41-42 (starred). A second region with a positive LOD = 1.52 was observed on chromosome 5. LOD scores for the remainder of the genome were negative.</p