Biallelic loss of TRAPPC9 function links vesicle trafficking pathway to autosomal recessive intellectual disability

Aslanger, Ayça Dilruba; Göncü, Beyza; Düzenli, Ömer Faruk; Yücesan, Emrah; Sengenc, Esma; Yeşil, Gözde

doi:10.1038/s10038-021-01007-8

Cited by 10 publications

(18 citation statements)

References 33 publications

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“…It is currently unclear how tissue-specific imprinting and maternal allele-biased expression of Trappc9 and Ago2 are regulated in the mouse brain. Furthermore, imprinting of the two genes is not conserved in humans ( Court et al, 2014 ) and only homozygous mutations of TRAPPC9 cause a neurodevelopmental disorder, which is characterized by intellectual disability, speech impairment and microcephaly ( Wilton et al, 2020 ; Aslanger et al, 2022 ). A potential mechanism could involve chromatin boundaries and CTCF-regulated access to tissue-specific enhancers as has been shown for the imprinted Igf2-H19 locus ( Bell and Felsenfeld, 2000 ).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the regulation of allelic expression of Trappc9 and Ago2 in NSCs is likely to differ from that in differentiated neural cells and might involve changes in histone modifications, transcription factor binding and/or enhancer access. In any case, a relevance of Trappc9 expression in NSCs is implied by the finding of reduced numbers of Sox2-positive stem cells in the subventricular zone and hippocampal subgranular zone of knock-out mice (Usman et al, 2022), which might be linked to their microcephaly phenotype (Ke et al, 2020;Liang et al, 2020;Wilton et al, 2020;Aslanger et al, 2022). Due to advances in technology, especially single-cell transcriptomics and highly sensitive in situ hybridization methods, it has now become possible to investigate imprinted gene expression on the cellular level (Varrault et al, 2020;Martini et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms underlying the predominantly maternal expression of these three genes in mouse brain are currently unclear. Trappc9 encodes a subunit of the intracellular trafficking protein particle II complex (TrappII), mutations of which lead to a neurodevelopmental disorder in humans and mice, which includes symptoms of postnatal microcephaly, intellectual disability and speech impairment ( Ke et al, 2020 ; Liang et al, 2020 ; Wilton et al, 2020 ; Aslanger et al, 2022 ). Ago2 forms a subunit of the RNA-induced silencing complex (RISC).…”

Section: Introductionmentioning

confidence: 99%

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Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Claxton

Pulix

Seah

et al. 2022

Front. Cell Dev. Biol.

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Genomic imprinting is an epigenetic process through which genes are expressed in a parent-of-origin specific manner resulting in mono-allelic or strongly biased expression of one allele. For some genes, imprinted expression may be tissue-specific and reliant on CTCF-influenced enhancer-promoter interactions. The Peg13 imprinting cluster is associated with neurodevelopmental disorders and comprises canonical imprinted genes, which are conserved between mouse and human, as well as brain-specific imprinted genes in mouse. The latter consist of Trappc9, Chrac1 and Ago2, which have a maternal allelic expression bias of ∼75% in brain. Findings of such allelic expression biases on the tissue level raise the question of how they are reflected in individual cells and whether there is variability and mosaicism in allelic expression between individual cells of the tissue. Here we show that Trappc9 and Ago2 are not imprinted in hippocampus-derived neural stem cells (neurospheres), while Peg13 retains its strong bias of paternal allele expression. Upon analysis of single neural stem cells and in vitro differentiated neurons, we find not uniform, but variable states of allelic expression, especially for Trappc9 and Ago2. These ranged from mono-allelic paternal to equal bi-allelic to mono-allelic maternal, including biased bi-allelic transcriptional states. Even Peg13 expression deviated from its expected paternal allele bias in a small number of cells. Although the cell populations consisted of a mosaic of cells with different allelic expression states, as a whole they reflected bulk tissue data. Furthermore, in an attempt to identify potential brain-specific regulatory elements across the Trappc9 locus, we demonstrate tissue-specific and general silencer activities, which might contribute to the regulation of its imprinted expression bias.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Claxton

Pulix

Seah

et al. 2022

Front. Cell Dev. Biol.

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“…It encodes a protein that has important roles in brain development and functions as an activator of NF-kappa-B through increased phosphorylation of the IκB kinase (IKK) complex [ 5 ]. The clinical spectrum related to TRAPPC9 mutations also include non-syndromic intellectual disability [ 14 ] autism [ 15 ] and severe developmental delay [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

A novel homozygous mutation in TRAPPC9 gene causing autosomal recessive non-syndromic intellectual disability

et al. 2022

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Background The etiology of intellectual disabilities is diverse and includes both genetic and environmental factors. The genetic causes of intellectual disabilities range from chromosomal aberrations to single gene disorders. The TRAPPC9 gene has been reported to cause autosomal recessive forms of intellectual disabilities in 56 patients from consanguineous and non-consanguineous families around the world. Methods We analyzed two siblings with intellectual disability, microcephaly and delayed motor and speech development from a consanguineous Sudanese family. Genomic DNA was screened for mutations using NGS panel (NextSeq500 Illumina) testing 173 microcephaly associated genes in the Molecular Genetics service in Robert Debre hospital in Paris, France. Results A novel homozygous mutation (NM_031466.7 (TRAPPC9):c.2288dup, p. (Val764Glyfs*7) in exon 14 of TRAPPC9 gene was found in the two patients. The mutation was predicted to cause nonsense mediated decay (NSMD) using SIFT prediction tool. The variant has not been found in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to the mutation. Conclusion This is the first study to report patients with TRAPPC9-related disorder from Sub-Saharan Africa.

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“…The appeal of human in vitro cell models stems from the potential to recapitulate and elucidate the pathophysiology of numerous diseases, including neurodegenerative disorders. Patient-derived cell lines can address cellular and molecular pathways that complement other experimental model systems, such as stress, autophagy, and trafficking [1][2][3]. The utility of patient-derived cell models depends upon their ability to reliably reflect normal or pathophysiological processes.…”

Section: Introductionmentioning

confidence: 99%

Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling

Argouarch

Schultz

Yang

et al. 2022

Stem Cell Rev and Rep

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Patient-derived cells hold great promise for precision medicine approaches in human health. Human dermal fibroblasts have been a major source of cells for reprogramming and differentiating into specific cell types for disease modeling. Postmortem human dura mater has been suggested as a primary source of fibroblasts for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols has not been fully established. In this study, cells derived from postmortem dura mater are directly compared to those from dermal biopsies of living subjects. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, striking differences were observed between cells of dermal and dural origin. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, slower growth rates, and a higher rate of karyotype abnormality. Dura mater-derived cells also failed to express fibroblast protein markers. When dermal fibroblasts and dura mater-derived cells from the same subject were compared, they exhibited highly divergent gene expression profiles that suggest dura mater cells originated from a mixed mural lineage. Given their postmortem origin, somatic mutation signatures of dura mater-derived cells were assessed and suggest defective DNA damage repair. This study argues for rigorous karyotyping of postmortem derived cell lines and highlights limitations of postmortem human dura mater-derived cells for modeling normal biology or disease-associated pathobiology. Graphical abstract

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Biallelic loss of TRAPPC9 function links vesicle trafficking pathway to autosomal recessive intellectual disability

Cited by 10 publications

References 33 publications

Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells

A novel homozygous mutation in TRAPPC9 gene causing autosomal recessive non-syndromic intellectual disability

Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling

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