A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia

Ciaccio, Claudia; Leonardi, Emanuela; Polli, Roberta; Murgia, Alessandra; D’Arrigo, Stefano; Granocchio, Elisa; Chiapparini, Luisa; Pantaleoni, Chiara; Esposito, Silvia

doi:10.1055/s-0041-1725964

Cited by 6 publications

(10 citation statements)

References 15 publications

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“…In noncarriers of APOE ε4, the EXOC6 gene was found to be associated with AD risk [70]. Interestingly, both KIRREL3 [58,62,[71][72][73][74][75][76][77] and EXOC6B [78][79][80] genes are also related to autism spectrum disorder (ASD), another cognitive disease with a young age of onset. Like neurodegenerative diseases, ASD is also associated with cerebral hypoperfusion [81], suggesting the presence of common brain endothelial pathologies in both diseases.…”

Section: Discussionmentioning

confidence: 99%

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

Wang,

Huang,

Ang

et al. 2024

Exploration of Medicine

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Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer’s disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. Methods: The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Results: Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). Conclusions: The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

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Section: Discussionmentioning

confidence: 99%

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

Wang,

Huang,

Ang

et al. 2024

Exploration of Medicine

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“…Interestingly, both KIRREL3 16,35,38,[45][46][47][48][49][50] and EXOC6B [51][52][53] genes are related to ASD, another cognitive disease with a young age of onset. Like neurodegenerative diseases, ASD is also associated with cerebral hypoperfusion, 54 suggesting the presence of common cerebrovascular pathologies in both diseases.…”

Section: Discussionmentioning

confidence: 99%

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

Wang

Huang

Ang

et al. 2023

Preprint

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Cerebrovascular damage coexists with Alzheimers disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, and APOE4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes: KIRREL3 rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001), KIRREL3 rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), and EXOC6B rs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g. KIRREL3 TT/CT or GG/GT carriers and EXOC6B GG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially in KIRREL3 and EXOC6B genotype carriers.

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“…We also found some genes with suggestive significance. For example, KIRREL3 is important for the development of nervous system, in particular for the process of neuronal migration, axonal fasciculation, and synapse formation [ 40 ]. Alterations of KIRREL3 have been linked to neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, and bipolar disorder [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The interaction of early life factors and depression-associated loci affecting the age at onset of the depression

et al. 2022

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Multiple previous studies explored the associations between early life factors and the age at onset of the depression. However, they only focused on the influence of environmental or genetic factors, without considering the interactions between them. Based on previous genome-wide association study (GWAS) data, we first calculated polygenic risk score (PRS) for depression. Regression analyses were conducted to assess the interacting effects of depression PRS and 5 early life factors, including felt hated by family member (N = 40,112), physically abused by family (N = 40,464), felt loved (N = 35633), and sexually molested (N = 41,595) in childhood and maternal smoking during pregnancy (N = 38,309), on the age at onset of the depression. Genome-wide environment interaction studies (GWEIS) were then performed to identify the genes interacting with early life factors for the age at onset of the depression. In regression analyses, we observed significant interacting effects of felt loved as a child and depression PRS on the age at onset of depression in total sample (β = 0.708, P = 5.03 × 10−3) and males (β = 1.421, P = 7.64 × 10−4). GWEIS identified a novel candidate loci interacting with felt loved as a child at GSAP (rs2068031, P = 4.24 × 10–8) and detected several genes with suggestive significance association, such as CMYA5 (rs7343, P = 2.03 × 10–6) and KIRREL3 (rs535603, P = 4.84 × 10–6) in males. Our results indicate emotional care in childhood may affect the age at onset of depression, especially in males, and GSAP plays an important role in their interaction.

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A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia

Cited by 6 publications

References 15 publications

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer’s disease in the Framingham Heart Study

Circulating Endothelial Progenitor Cells Reduce the Risk of Alzheimer’s Disease

The interaction of early life factors and depression-associated loci affecting the age at onset of the depression

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