Risk gene-set and pathways in 22q11.2 deletion-related schizophrenia: a genealogical molecular approach

Michaelovsky, Elena; Carmel, Miri; Frisch, Amos; Salmon‐Divon, Mali; Pasmanik‐Chor, Metsada; Weizman, Abraham; Gothelf, Doron

doi:10.1038/s41398-018-0354-9

Cited by 13 publications

(6 citation statements)

References 66 publications

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“…For example, PRS for schizophrenia showed associations for a number of traits including poor cognitive outcomes ( 71 ) but also enhanced creativity ( 72 ), language performance ( 73 ) and hearing ( 74 ). Similarly, PRSs for general cognitive abilities show effects on reading and language measures ( 15 , 75–77 ).…”

Section: Discussionmentioning

confidence: 96%

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

Martinelli

Rice

Talcott

et al. 2021

Human Molecular Genetics

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At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum p = 0.002 for nonword reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

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Section: Discussionmentioning

confidence: 96%

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

Martinelli

Rice

Talcott

et al. 2021

Human Molecular Genetics

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“…It is intriguing to speculate that the golgi localization of ACSF2 in cells of neural origin may be important for neurodevelopment. In support of this possibility, Michaelovsky et al reported a possible association between ACSF2 copy number variation and missense mutations in schizophrenia and neurodevelopment [55].…”

Section: Discussionmentioning

confidence: 99%

ACSF2: A MEDIUM-CHAIN ACYL-CoA SYNTHETASE WITH A POTENTIAL ROLE IN NEURONAL DIFFERENTIATION

Maiguel

Morita

Pei

et al. 2022

Preprint

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By activating fatty acids to their CoA derivatives, acyl CoA synthetases (ACS) play an essential role in fatty acid metabolism. We previously identified ACSF2 as an ACS that was phylogenetically distinct from known families of short-chain, medium-chain, long-chain, very long-chain, and bubblegum ACSs. Functionally, ACSF2 preferentially activated medium-chain fatty acids. In this work, we provide further characterization of this unique ACS. ACSF2 mRNA expression was found in most tissues, although immunohistochemical analysis revealed differences in protein expression between various cell types in each tissue. Endogenous ACSF2 was found in the Golgi region in Neuro2a and P19 cells, and disruption of the Golgi in Neuro2a cells with nocodazole disrupted ACSF2 localization. In contrast, MA-10, HepG2, and skin fibroblasts had a mitochondrial ACSF2 localization. ACSF2 activated saturated fatty acids containing 6 to 10 carbons when overexpressed in COS-1 cells. The Kmapp for C10:0 was 24.4 mM and Vmaxapp was 385 nmol/20min/mg COS cell protein. Knockdown by RNA interference revealed that ACSF2 was responsible for most of the medium-chain ACS activity in Neuro2a cells. A lysine residue critical for activity in bacterial short-chain ACSs was found in ACSF2, and mutation of this residue to alanine abolished enzyme activity. Neurite outgrowth results when Neuro2a cells are induced to differentiate with retinoic acid, and ACSF2 migrated to nodes and points of neurite-neurite contact along with the presynaptic marker, synaptophysin. ACSF2 deficient Neuro2a cells showed significantly blunted neurite outgrowth in response to retinoic acid. These results suggest that this medium-chain ACS may play an important role in neuronal development.

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“…Recently, research efforts have shifted towards studying two-hit or multihit hypotheses to explain variable penetrance in 22q11DS. Emerging data suggest that common and rare variants in the intact (non-deleted) chromosome may affect proclivity towards psychosis [ 45 ], or Parkinson’s disease in some families with 22q11DS [ 46 ]. For example, other rare CNVs elsewhere in the genome may confer additional risk for adverse outcomes in 22q11DS [ 47 , 48 ].…”

Section: Q112 Deletion Syndrome As a Model For Studying Neuropsychmentioning

confidence: 99%

Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome

Fiksinski

Schneider

Zinkstok

et al. 2021

Curr Psychiatry Rep

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Purpose of Review The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond. Recent Findings We will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective. Summary We outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.

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Risk gene-set and pathways in 22q11.2 deletion-related schizophrenia: a genealogical molecular approach

Cited by 13 publications

References 66 publications

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

ACSF2: A MEDIUM-CHAIN ACYL-CoA SYNTHETASE WITH A POTENTIAL ROLE IN NEURONAL DIFFERENTIATION

Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome

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