KIF1B and NF1 are the most frequently mutated genes in paraganglioma and pheochromocytoma tumors

Evenepoel, Lucie; Helaers, Raphaël; Vroonen, Laurent; Aydın, Selda; Hamoir, Marc; Maiter, Dominique; Vikkula, Miikka; Persu, Alexandre

doi:10.1530/erc-17-0061

Cited by 17 publications

(6 citation statements)

References 10 publications

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“…The gene product of KIF1B is a postulated tumour suppressor with a role in an apoptotic pathway induced by neurotrophin deprivation [21]. While KIF1B was found to be the second most frequently mutated gene in a multicentric Belgian PPGL patient cohort [26], the T827I mutation in exon 24 of the KIF1Bβ-isoform has hitherto only previously been described in a paraganglioma [26] and a neuroblastoma [21]. Assuming that KIF1B is a tumour suppressor, the T827I variant's pathogenicity for hPheo1 appears uncertain since Sanger sequencing of cDNA with an amplicon spanning exons 23−25 showed that mutant and wildtype alleles are both expressed (Supplementary Figure S1), and thereby that the wildtype allele is retained.…”

Section: Hpheo1 Is Heterozygous For Nras Q61k and Expresses The Mutant Allelementioning

confidence: 96%

Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma

Rossitti

Dutta

Ghayee

et al. 2020

IJMS

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Phaeochromocytomas and paragangliomas (PPGLs) are neuroendocrine catecholamine-producing tumours that may progress into inoperable metastatic disease. Treatment options for metastatic disease are limited, indicating a need for functional studies to identify pharmacologically targetable pathophysiological mechanisms, which require biologically relevant experimental models. Recently, a human progenitor phaeochromocytoma cell line named “hPheo1” was established, but its genotype has not been characterised. Performing exome sequencing analysis, we identified a KIF1B T827I mutation, and the oncogenic NRAS Q61K mutation. While KIF1B mutations are recurring somatic events in PPGLs, NRAS mutations have hitherto not been detected in PPGLs. Therefore, we aimed to assess its implications for the hPheo1 cell line, and possible relevance for the pathophysiology of PPGLs. We found that transient downregulation of NRAS in hPheo1 led to elevated expression of genes associated with cell adhesion, and enhanced adhesion to hPheo1 cells’ extracellular matrix. Analyses of previously published mRNA data from two independent PPGL patient cohorts (212 tissue samples) revealed a subcluster of PPGLs featuring hyperactivated RAS pathway-signalling and under-expression of cell adhesion-related gene expression programs. Thus, we conclude that NRAS activity in hPheo1 decreases adhesion to their own extracellular matrix and mirrors a transcriptomic RAS-signalling-related phenomenon in PPGLs.

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Section: Hpheo1 Is Heterozygous For Nras Q61k and Expresses The Mutant Allelementioning

confidence: 96%

Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma

Rossitti

Dutta

Ghayee

et al. 2020

IJMS

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“…Indeed, MBNL1 CLIP tags appear throughout the Ncl mRNA, and it may be translationally repressed while transported by kinesins. Thus, this circuit may control cell size during neurogenesis and potentially even modulate susceptibility to cancer, as mutations connected to KIF1B have been implicated in neuroblastomas (Yang et al, 2001), paragangliomas, and pheochromocytomas (Evenepoel et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes

Hildebrandt

Moss

Janusz-Kaminska

et al. 2022

Preprint

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RNA transport and local translation provide spatial control of gene expression, and RNA binding proteins (RBPs) act as critical adapters in this multi-step process. Muscleblind-like (MBNL) RNA binding proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and distal neurites through unknown mechanisms. We found that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα ; and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs also associate with these kinesins, implicating a motor-RBP specificity code. Live cell imaging and fractionation revealed that membrane anchoring is mediated through the unstructured carboxy-terminal tail of MBNL1. Both kinesin- and membrane-recruitment functions were reconstituted using MBNL-MS2 coat protein fusions. This approach, termed RBP Module Recruitment and Imaging (RBP-MRI), decouples RNA binding, kinesin recruitment, and membrane anchoring functions, while also establishing general strategies for studying multi-functional, modular domains of RBPs.

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“…In this study, the most frequently somatically mutated genes in PCC were NF1 (20.8 %) and KIF1B (20.4 %). No significant difference in the proportion of KIF1B mutations was observed between PCC and PGL (46 % vs. 30 %) [71]. Yeh et al described germline KIF1Bbeta mutations in a family with neural and non-neural tumors.…”

Section: Kinesin Family Member 1bmentioning

confidence: 99%

An Update on the Histology of Pheochromocytomas: How Does it Relate to Genetics?

et al. 2018

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Pheochromocytomas are rare neuroendocrine tumors of the adrenal gland, whereas any extra-adrenal tumor with similar histology is designated as paraganglioma. These tumors have a very high rate of germline mutations in a large number of genes, up to 35% to 40%, frequently predisposing for other tumors as well. Therefore, they represent a phenomenal challenge for treating physicians. This review focuses on pheochromocytomas only, with special attention to gross and microscopic clues to the diagnosis of genetic syndromes, including the role of succinate dehydrogenase subunit A and subunit B immunohistochemistry as surrogate markers for genetic analysis in the field of succinate dehydrogenase subunit gene mutations.

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KIF1B and NF1 are the most frequently mutated genes in paraganglioma and pheochromocytoma tumors

Cited by 17 publications

References 10 publications

Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma

Activation of RAS Signalling is Associated with Altered Cell Adhesion in Phaeochromocytoma

Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes

An Update on the Histology of Pheochromocytomas: How Does it Relate to Genetics?

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