A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

Mohamoud, Hussein Sheikh Ali; Ahmed, Saleem; Jelani, Musharraf; Alrayes, Nuha; Childs, Kay; Vadgama, Nirmal; Almramhi, Mona Mohammad; Al‐Aama, Jumana Y.; Goodbourn, Stephen; Nasir, Jamal

doi:10.1038/s41598-018-20658-w

Cited by 33 publications

(36 citation statements)

References 34 publications

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“…It remains unclear what role TRAPPC6A1 plays in the etiology of AD. A TRAPPC6A2 missense variant was recently reported in individuals with a clinical spectrum including intellectual deficit, speech delay, polydactyly and facial dysmorphism . The variant was one of five homozygous variants detected in these individuals, all of which are rare and predicted to be pathogenic.…”

Section: Trappopathies: Diseases Associated With Variants In Trapp Prmentioning

confidence: 96%

TRAPPopathies: An emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)‐associated proteins

Sacher

Shahrzad

Kamel

et al. 2018

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The movement of proteins between cellular compartments requires the orchestrated actions of many factors including Rab family GTPases, Soluble NSF Attachment protein REceptors (SNAREs) and so-called tethering factors. One such tethering factor is called TRAnsport Protein Particle (TRAPP), and in humans, TRAPP proteins are distributed into two related complexes called TRAPP II and III. Although thought to act as a single unit within the complex, in the past few years it has become evident that some TRAPP proteins function independently of the complex. Consistent with this, variations in the genes encoding these proteins result in a spectrum of human diseases with diverse, but partially overlapping, phenotypes. This contrasts with other tethering factors such as COG, where variations in the genes that encode its subunits all result in an identical phenotype. In this review, we present an up-to-date summary of all the known disease-related variations of genes encoding TRAPP-associated proteins and the disorders linked to these variations which we now call TRAPPopathies.

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Section: Trappopathies: Diseases Associated With Variants In Trapp Prmentioning

confidence: 96%

TRAPPopathies: An emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)‐associated proteins

Sacher

Shahrzad

Kamel

et al. 2018

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“…Many mutations in the TRAPP complex also have been identified in patients (see also Table 1). Mutations in TRAPPC6A, TRAPPC6B, and TRAPPC9 are observed in patients with neurodevelopmental disorders [91][92][93][94]. TRAPPC2L and TRAPPC12 mutations cause encephalopathy [95,96].…”

Section: Er-to-golgi Trafficking Defects and Neurological Disordersmentioning

confidence: 99%

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

Wang

Stanford

Kundu

2020

Cells

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Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. OverviewApproximately one-third of all proteins encoded by the mammalian genome are exported from the endoplasmic reticulum (ER) and transported to the Golgi apparatus, where they are sorted for delivery to their final destination in membrane compartments or secretory vesicles [1]. Secretory proteins are co-translationally inserted into the ER and then packaged into transport vesicles at ER exit sites (ERES, also known as the transitional ER), which are specialized regions of smooth ER [1].The stepwise process for segregating and exporting cargo from the ER is similar in yeast, plant, and mammalian cells and relies on several essential proteins (SAR1-GTPase, SEC23, SEC24, SEC13, and SEC31). The first step involves the conversion of SAR1-GDP to SAR1-GTP by the guanine nucleotide exchange factor SEC12, which resides in the ER membrane [2,3]. This results in the localization of SAR1-GTP to the ER membrane, triggering the recruitment of SEC23/24 heterodimers [4]. The membrane localization of the SEC23/24 heterodimers promotes the entrapment of cargo by SEC24 and the recruitment of SEC13/31 heterotetramers. The sequential binding of SEC13/31 heterotetramers to SAR1-GTP-SEC23/24 complexes drives the formation of a cage-like lattice [4][5][6][7]. Although the basic steps involved in generating COPII vesicles are well understood and can be reconstituted in vitro, additional proteins are involved in regulating the process in cells. Differences between yeast and mammalian ER-to-Golgi trafficking include the presence of multiple COPII protein isoforms and an ER-Golgi intermediate compartment (ERGIC) in mammals, which likely evolved to help meet the cell-type-specific demands of multicellular organisms.Unlike other cell types, neurons consist of two compartments: the somatodendritic compartment and the axonal compartment. These compartments are separated by the axonal-exclusion zone located at the base of the axon, where proteins are either permitted into or excluded from the axon. Neurons are

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“…The domain architecture of TRAPPC9 protein exhibits ASH domains, identified by reciprocal HHpred searches, and TPR repeat regions, identified by HHpred and TPRpred. Adapted from Ref (4). TRAPPC9, trafficking protein particle complex 9; ASH, ASPM, SPD-2, Hydin; TPR, tetratricopeptide.…”

Section: Nf-κbmentioning

confidence: 99%

“…In addition, TRAPPC9 has been reported to bind and interact with p150(Glued) at the trans-Golgi region (3). Studies have also suggested that mutations in TRAPPC9 are linked with a form of mental retardation (MR) associated with severe osseous deformities, including short stature and polydactylism (4). Clinical phenotypes associated with TRAPPC9 mutation have been linked with decreased activation of nuclear factor-κB (NF-κB).…”

Section: Introductionmentioning

confidence: 99%

TRAPPC9: Novel insights into its trafficking and signaling pathways in health and disease (Review)

et al. 2018

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Trafficking protein particle complex 9 (TRAPPC9) is a protein subunit of the transport protein particle II (TRAPPII), which has been reported to be important in the trafficking of cargo from the endoplasmic reticulum (ER) to the Golgi, and in intra-Golgi and endosome-to-Golgi transport in yeast cells. In mammalian cells, TRAPPII has been shown to be important in Golgi vesicle tethering and intra-Golgi transport. TRAPPC9 is considered to be a novel molecule capable of modulating the activation of nuclear factor-κB (NF-κB). Mutations in TRAPPC9 have been linked to a rare consanguineous hereditary form of mental retardation, as part of the NF-κB pathways. In addition, TRAPPC9 has been reported to be involved in breast and colon cancer and liver diseases. The present review highlights the most recent publications on the structure, expression and function of TRAPPC9, and its association with various human diseases.

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A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features

Cited by 33 publications

References 34 publications

TRAPPopathies: An emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)‐associated proteins

TRAPPopathies: An emerging set of disorders linked to variations in the genes encoding transport protein particle (TRAPP)‐associated proteins

ER-to-Golgi Trafficking and Its Implication in Neurological Diseases

TRAPPC9: Novel insights into its trafficking and signaling pathways in health and disease (Review)

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