A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with ...late-onset Alzheimer’s disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing, and the resulting isogenic pair of iPSC lines was differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3-dimensional morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant.
Abstract Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and ...amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects ( p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0–23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.
Introduction:
This article discusses agomelatine (Valdoxan™/Thymanax™; Servier/Novartis), which is a melatonin (MT1/MT2) agonist and serotonin (5-HT2c) receptor antagonist. Agomelatine has been ...approved for the treatment of adults with major depression by several regulatory agencies and is now on the market in 41 countries.
Areas covered:
Literature related to agomelatine was reviewed on PubMed using the search terms 'agomelatine OR S-20098' and 204 articles were found. Twelve published, randomized, double-blind studies were included in this review.
Expert opinion:
Agomelatine produces strong effects on circadian sleep phase disturbances, improving time to sleep onset and quality of sleep. It has been shown to be superior to placebo and similar to existing antidepressants, as demonstrated by short-term clinical trials and one relapse prevention trial. However, 0 - 0.6% and 3 - 4.5% of patients treated with 25 and 50 mg, respectively, showed elevated transaminases. Although none of these reactions so far seem to have been serious, the adverse effects in the liver may present a regulatory and marketing challenge. Given equivalence or modest superiority to existing, generic alternatives, the acceptability in a third-party reimbursement environment is questionable. Future clinical trials are needed to establish an appropriate market niche.
To characterize the clinical and molecular effect of mutations in the sortilin-related receptor (
) gene.
We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset ...Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with
mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with
mutations.
alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking.
The findings from this study support an important role for
mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and
mutations merits further investigation.
Abstract African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide ...association study in AAs to date confirmed that six of the Alzheimer's disease (AD)–related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7 ) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.
Abstract Introduction Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. Methods We performed genome-wide linkage and ...identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. Results Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds LOD* ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177 , and the microRNA Mir_320 , whereas IBD analyses implicates an additional gene BCL11B , a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
Rett disorder and autistic disorder are both pervasive developmental disorders. Recent studies indicate that at least 80% of Rett Disorder cases are caused by mutations in the methyl-CpG-binding ...protein 2 (MeCP2) gene. Since there is some phenotypic overlap between autistic disorder and Rett disorder, we analyzed 69 females clinically diagnosed with autistic disorder for the presence of mutations in the MeCP2 gene. Two autistic disorder females were found to have de novo mutations in the MeCP2 gene. These data provide additional evidence of variable expression in the Rett disorder phenotype and suggest MeCP2 testing may be warranted for females presenting with autistic disorder.
Abstract Background The Arg406Trp (R406W) missense mutation in the microtubule-associated protein-tau gene (MAPT ) is a known cause of early-onset dementia. Various dementia phenotypes have been ...described, including frontotemporal dementia (FTD), FTD with parkinsonism, and early-onset Alzheimer disease (EOAD)-like presentations. Methods Using whole-exome capture with subsequent sequencing, we identified the R406W mutation in a family with multiple individuals with clinically diagnosed EOAD, in a pattern suggesting autosomal dominant inheritance. We reevaluated all available family members clinically. Results Each of the affected individuals had a course meeting clinical criteria for EOAD. Two distinct disease trajectories were apparent: one rapidly progressive, and the other long and gradual. Four of five affected individuals also manifested parkinsonian symptoms. FTD features were not prominent and, when present, appeared only late in the course of dementia. Conclusions The MAPT R406W mutation is associated with EOAD-like symptoms and parkinsonism without FTD, as well as distinct cognitive courses.
The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to ...the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk.
Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls.
We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family.
The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.
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