Familial dorsalization of the skin of the proximal palm and the instep of the sole of the foot

Al-Qattan, M. M.; Shamseldin, Hanan E.; Alkuraya, Fowzan S.

doi:10.1016/j.gene.2012.03.009

Cited by 11 publications

(8 citation statements)

References 16 publications

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“…In addition to LCCS1, human genetic linkage analysis has identified additional GLE1 causal mutations that result in the Lethal Arthrogryposis with Anterior horn cell disease (Nousiainen et al, 2008). Further, recent deep sequencing studies report gle1 mutant alleles in other human diseases (Al-Qattan et al, 2012; Tzschach et al, 2012). For these diseases, it is unclear whether or how hGle1 has cell type specific effects.…”

Section: Discussionmentioning

confidence: 99%

Gle1 Functions during mRNA Export in an Oligomeric Complex that Is Altered in Human Disease

Folkmann

Collier

Zhan

et al. 2013

Cell

114

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The conserved multifunctional protein Gle1 regulates gene expression at multiple steps: nuclear messenger (m)RNA export, translation initiation, and translation termination. A GLE1 mutation (FinMajor) is causally linked to human lethal congenital contracture syndrome-1 (LCCS1); however, the resulting perturbations on Gle1 molecular function were unknown. FinMajor results in a Proline-Phenylalanine-Glutamine peptide insertion within the uncharacterized Gle1 coiled-coil domain. Here we find that Gle1 self-associates both in vitro and in living cells via the coiled-coil domain. Electron microscopy reveals high molecular mass Gle1 oligomers form ∼26 nm in diameter disk-shaped particles. With the Gle1-FinMajor protein, these particles are malformed. Moreover, functional assays document a specific requirement for proper Gle1 oligomerization during mRNA export but not for Gle1’s roles in translation. These results identify a novel mechanistic step in Gle1’s mRNA export function at nuclear pore complexes, and directly implicate altered export in LCCS1 disease pathology.

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Section: Discussionmentioning

confidence: 99%

Gle1 Functions during mRNA Export in an Oligomeric Complex that Is Altered in Human Disease

Folkmann

Collier

Zhan

et al. 2013

Cell

114

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“…Almost all patients with lethal congenital contracture syndrome carry homozygous copies of the Fin Major allele. Furthermore, a dominant missense mutation in GLE1 (p.R584W) is associated with dorsalization of the hands and feet by an unknown pathomechanism ( Al-Qattan et al , 2012 ).…”

Section: Early-onset Conditionsmentioning

confidence: 99%

Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

Peeters

Chamova

Jordanova

2014

Brain

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“…It is possible that alleles specific for Gle1 translation roles might have other pathologies. Interestingly, mutations in hGLE1 have also been linked to a hand and foot dorsalization disease, but both the physiological and molecular underpinnings of this phenotype are yet to be resolved (Al-Qattan et al, 2012). Given the large spectrum of proteins and signaling factors that regulate each gene expression transition point, we predict that aberrant mRNP remodeling will play a role in other RNA metabolism-linked disease states.…”

Section: Discussionmentioning

confidence: 99%

Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure–function analysis

Folkmann

Dawson

Wente

2014

Advances in Biological Regulation

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A critical step during gene expression is the directional export of nuclear messenger (m)RNA through nuclear pore complexes (NPCs) to the cytoplasm. During export, Gle1 in conjunction with inositol hexakisphosphate (IP6) spatially regulates the activity of the DEAD-box protein Dbp5 at the NPC cytoplasmic face. GLE1 mutations are causally linked to the human diseases lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn cell disease (LAAHD). Here, structure prediction and functional analysis provide strong evidence to suggest that the LCCS1 and LAAHD disease mutations disrupt the function of Gle1 in mRNA export. Strikingly, direct fluorescence microscopy in living cells reveals a dramatic loss of steady-state NPC localization for GFP-gle1 proteins expressed from human gle1 genes harboring LAAHD and LCCS1 mutations. The potential significance of these residues is further clarified by analyses of sequence and predicted structural conservation. This work offers insights into the perturbed mechanisms underlying human LCCS-1 and LAAHD disease states and emphasizes the potential impact of altered mRNA transport and gene expression in human disease.

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Familial dorsalization of the skin of the proximal palm and the instep of the sole of the foot

Cited by 11 publications

References 16 publications

Gle1 Functions during mRNA Export in an Oligomeric Complex that Is Altered in Human Disease

Gle1 Functions during mRNA Export in an Oligomeric Complex that Is Altered in Human Disease

Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure–function analysis

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