RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes

Brownstein, Catherine A.; Smith, Richard; Rodan, Lance H.; Gorman, Mark; Hojlo, Margaret A.; Garvey, Emily; Li, Jianqiao; Cabral, Kristin; Bowen, Joshua; Rao, A. Venketeshwer; Genetti, Casie A.; Carroll, Devon; Deaso, Emma; Agrawal, Pankaj B.; Rosenfeld, Jill A.; Bi, Weimin; Howe, Jennifer; Stavropoulos, Dimitri J.; Hansen, Adam W.; Hamoda, Hesham M.; Pinard, Ferne; Caracansi, Annmarie; Walsh, Christopher A.; D’Angelo, Eugene J.; Beggs, Alan H.; Zarrei, Mehdi; Gibbs, Richard A.; Scherer, Stephen W.; Glahn, David C.; Gonzalez–Heydrich, Joseph

doi:10.1038/s41380-021-01035-y

Cited by 12 publications

(11 citation statements)

References 67 publications

(73 reference statements)

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“…And its deficiency may upregulate the expression of genes responsible for ribosome biogenesis. Meanwhile, we also found that Rcl1 protein was distributed in both nucleus and cytoplasm of HCC cell and hepatocyte lines by immunofluorescence, which is consistent with a recent study [31]. Notably, the cytoplasmic Rcl1 protein level of HCC cell lines was dramatically reduced compared to hepatocyte cell.…”

Section: Discussionsupporting

confidence: 91%

Rcl1 suppresses tumor progression of hepatocellular carcinoma: a comprehensive analysis of bioinformatics and in vitro experiments

Hou

Yang

et al. 2022

Cancer Cell Int

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Background RNA 3’-terminal phosphate cyclase-like protein (Rcl1) is involved in pre-rRNA processing, but its implication in cancers remains unclear. Methods RCL1 expressions in 21 malignancies was examinated through GEPIA website portal. Clinical implication data related to RCL1 level in Hepatocellular Carcinoma (HCC) samples were downloaded through TCGA, ICGC, GEO databases. Survival analysis and gene function enrichment analyses were performed through R software. The correlation between RCL1 expression and tumor immune infiltration was assessed via the TIMER2.0 database. The effects of Rcl1 overexpression or knockdown on cell growth and metastasis was evaluated by CCK8, transwell, and cell cycle assays. Results RCL1 expression is commonly down-regulated in HCC. The lower expression of RCL1 is associated with higher tumor stage, higher AFP level, vascular invasion, and poor prognosis. RCL1 expression has a significant correlation with immune cells infiltration in HCC, especially myeloid-derived suppressor cell (MDSC). Moreover, it was further identified that Rcl1 expression was reduced in HCC cell lines and negatively correlated with invasion of HCC cell lines. Immunofluorescence (IF) analysis revealed that the level of Rcl1 expression in the cytoplasm of HCC cells is significantly lower than that in the cytoplasm of L-02 cell. Moreover, both gain- and loss-of-function studies demonstrated that Rcl1 inhibited the growth and metastasis of HCC cells and regulated cell cycle progression in vitro. Conclusions Rcl1 may serve as a novel tumor suppressor in HCC, and its biological effect needs further study.

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Section: Discussionsupporting

confidence: 91%

Rcl1 suppresses tumor progression of hepatocellular carcinoma: a comprehensive analysis of bioinformatics and in vitro experiments

Hou

Yang

et al. 2022

Cancer Cell Int

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“…20 Disruptions in SEZ6L cause neurodevelopmental, psychiatric, and neurodegenerative conditions, as well as having a role in motor function. 20, 55, 56 Copy number variation in RCL1 , has also been associated with severe psychiatric disease, 57 and depression. 58 Progressive synaptic loss, or synaptopathy, is a hallmark of MS pathology; 59, 60 evident in both acutely active demyelinating lesions, 61 as well as chronic inactive lesions.…”

Section: Discussionmentioning

confidence: 99%

Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement

Jokubaitis

Ibrahim

Stankovich

et al. 2022

Preprint

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Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped individuals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 individuals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 - 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.

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“…Both RCL1 haploinsufficiency and bi‐allelic variants in CAPN1 have been associated with a variety of psychiatric symptoms 5,6,19 . SPG76 shows a wide phenotypic spectrum with pure and complex forms and significant inter‐ and intra‐familial variability 4,6,20–23 .…”

Section: Discussionmentioning

confidence: 99%

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

Alecu

Saffari

Jumo

et al. 2022

Ann Clin Transl Neurol

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CAPN1‐associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain‐1 function. Here we illustrate a translational approach to the case of an 18‐year‐old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound‐heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop‐gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain‐1 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.

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RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes

Cited by 12 publications

References 67 publications

Rcl1 suppresses tumor progression of hepatocellular carcinoma: a comprehensive analysis of bioinformatics and in vitro experiments

Rcl1 suppresses tumor progression of hepatocellular carcinoma: a comprehensive analysis of bioinformatics and in vitro experiments

Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

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