A homozygous founder mutation in<i>TRAPPC6B</i>associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features

Marin‐Valencia, Isaac; Novarino, Gaia; Johansen, Anide; Rosti, Basak; Issa, Mahmoud Y.; Musaev, Damir; Bhat, Gifty; Scott, Eric; Silhavy, Jennifer L.; Stanley, Valentina; Rosti, Rasim Özgür; Gleeson, Jeremy W; Imam, Farhad; Zaki, Maha S.; Gleeson, Joseph G.

doi:10.1136/jmedgenet-2017-104627

Cited by 44 publications

(32 citation statements)

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“…Recently, bi-allelic disease-causing variants in TRAPPC12 (MIM: 614139) were shown to cause progressive childhood encephalopathy with brain abnormalities 10. Finally, a founder homozygous splice variant in TRAPPC6B (MIM: 610397) was reported to cause a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features 40. It is thus emerging that TRAPP dysfunction contributes significantly to human neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

et al. 2018

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“…This is of interest given the interaction between the yeast homologues for TRAPPC6 and TRAPPC9 (Trs33 and Trs120, respectively; see above). A second report identified TRAPPC6B splice variants in six individuals from three unrelated consanguineous families of Egyptian origin . All affected individuals had similar phenotypes that included microcephaly, epilepsy and brain malformations including atrophy and thinning of the corpus callosum.…”

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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“…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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A homozygous founder mutation inTRAPPC6Bassociates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features

Cited by 44 publications

References 20 publications

Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

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

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