Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene

Denier, Christian; Balu, Laurent; Husson, B.; Nasser, G.; Bürglen, Lydie; Rodriguez, Diana; Labauge, Pierre; Chevret, L.

doi:10.1016/j.jns.2014.07.025

Cited by 25 publications

(26 citation statements)

References 10 publications

(26 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cell-type selective functions of Ranbp2 likely stem from the control of nucleocytoplasmic shuttling, proteostasis or post-translational modifications of cell-type selective, stress-elicited or disease-prone substrates, such as hnRNPA2B1, parkin, M-opsin and Stat3, by unrelated domains of Ranbp2 that are interspersed between its RBDs (Cho et al, 2015a, 2014; Patil et al, 2014; Um et al, 2006; Wälde et al, 2012; Hamada et al, 2011). This view is also supported by mounting genetic evidence in humans with clinically restricted neurological maladies triggered by selective stressors and mutations in the leucine-rich domain of RANBP2 (Neilson et al, 2009; Wolf et al, 2013; Denier et al, 2014). Furthermore, mutations that uncouple selective RBDs of Ranbp2 from Ran GTPase, Ranbp2 haploinsufficiency or mutations impairing the SUMO-binding motif of Ranbp2 promote neural-type restricted phenotypes in the absence or presence of noxious stressors in mice (Patil et al, 2014; Cho et al, 2010, 2015a).…”

Section: Introductionmentioning

confidence: 90%

Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes

Cho

Yoon

Qiu

et al. 2017

Disease Models &Amp; Mechanisms

102

View full text Add to dashboard Cite

The pathogenic drivers of sporadic and familial motor neuron disease (MND), such amyotrophic lateral sclerosis (ALS), are unknown. MND impairs the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology have remained elusive. The cytosolic and peripheral nucleoporin Ranbp2 is a crucial regulator of the Ran GTPase cycle and of the proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation of Ranbp2 in mouse Thy1 motoneurons causes ALS syndromes with hypoactivity followed by hindlimb paralysis, respiratory distress and, ultimately, death. These phenotypes are accompanied by: a decline in the nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve; a reduction in the g-ratios of sciatic and phrenic nerves; and hypertrophy of motoneurons. Furthermore, Ranbp2 loss disrupts the nucleocytoplasmic partitioning of the import and export nuclear receptors importin β and exportin 1, respectively, Ran GTPase and histone deacetylase 4. Whole-transcriptome, proteomic and cellular analyses uncovered that the chemokine receptor Cxcr4, its antagonizing ligands Cxcl12 and Cxcl14, and effector, latent and activated Stat3 all undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation as a result of Ranbp2 loss in motoneurons. These effects were accompanied by paracrine and autocrine neuroglial deregulation of hnRNPH3 proteostasis in sciatic nerve and motoneurons, respectively, and post-transcriptional downregulation of metalloproteinase 28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase 28 signaling, and proteostasis of substrates that are crucial to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes.

show abstract

Section: Introductionmentioning

confidence: 90%

Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes

Cho

Yoon

Qiu

et al. 2017

Disease Models &Amp; Mechanisms

102

View full text Add to dashboard Cite

show abstract

“…Despite the broad expression of Ranbp2, heterogeneous genetic changes in Ranbp2 underlie insidious or pervasive expressions of diseases or traits affecting restricted cell types or tissues. For example, asymptomatic and selective semi-dominant mutations in RANBP2 cause necrotic encephalopathy upon exposure to selective infectious agents [28][29][30][31], whereas haploinsufficiency of Ranbp2 promotes carcinogenesis [24], deficits in glucose metabolism upon glucose challenge [27], MPTP-elicited parkinsonism [32], and neuroprotection of photoreceptor neurons to light damage in mice [10,33]. However, the modular activities of Ranbp2 that contribute to stress-dependent and cell-type restricted expressions of these pathological traits remain to be defined.…”

Section: Introductionmentioning

confidence: 99%

Uncoupling phototoxicity‐elicited neural dysmorphology and death by insidious function and selective impairment of Ran‐binding protein 2 (Ranbp2)

et al. 2015

View full text Add to dashboard Cite

Morphological disintegration of neurons is coupled invariably to neural death. In particular, disruption of outer segments of photoreceptor neurons triggers photoreceptor death regardless of the pathological stressors. We show that Ranbp2−/−::Tg-Ranbp2CLDm mice with mutations in SUMO-binding motif (SBM) of cyclophilin-like domain (CLD) of Ranbp2 expressed in a null Ranbp2 background lack untoward effects in photoreceptors in the absence of light-stress. However, compared to wild type photoreceptors, light-stress elicits profound disintegration of outer segments of Ranbp2−/−::Tg-Ranbp2CLDm with paradoxical age-dependent resistance of photoreceptors to death and genotype-independent caspase activation. Ranbp2−/−::Tg-Ranbp2CLDm exhibit photoreceptor death-independent changes in ubiquitin-proteasome system (UPS), but death-dependent increase of ubc9 levels. Hence, insidious functional impairment of SBM of Ranbp2’s CLD promotes neuroprotection and uncoupling of photoreceptor degeneration and death against phototoxicity.

show abstract

“…Although MRI findings of our patients did not fit those of acute necrotizing encephalopathy (ANE), in order to further clarify the genetic predisposition, we proposed genetic analysis for the gene encoding nuclear pore protein Ran Binding Protein 2 ( RANBP2 ), which has been reported in cases of recurrent or familial ANE; 8 , 9 however, the family declined the genetic studies.…”

Section: Case Report #2mentioning

confidence: 88%

Mild Encephalopathy with Reversible Lesions in the Splenium of Corpus Callosum and Bilateral Cerebral Deep white Matter in Identical twins

et al. 2016

View full text Add to dashboard Cite

Identical twin brothers developed mild encephalopathy at the age of 7.0 and 9.7 years (Patient 1) and 10.7 years (Patient 2). Patient 1 had influenza A at the time of his second episode, but triggering agents were not evident at the first episode. The triggering agents in Patient 2 were unclear. The neurological features of both patients included transient facial numbness, left arm paresis, dysarthria, and gait disturbance. Diffusion-weighted images from magnetic resonance imaging showed high signal levels at the splenium of corpus callosum and in the bilateral cerebral deep white matter. These results are characteristic of mild encephalitis/encephalopathy with a reversible isolated splenium of corpus callosum lesion. All three episodes were treated with a methylprednisolone pulse. Acyclovir was also administered to Patient 2 and to Patient 1 during his first episode. Patient 1 received an anti-influenza agent and intravenous immunoglobulin during his second episode. Both patients recovered completely without sequelae. Genetic factors, which may predispose identical twins to develop encephalopathy, are discussed.

show abstract

Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene

Cited by 25 publications

References 10 publications

Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes

Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes

Uncoupling phototoxicity‐elicited neural dysmorphology and death by insidious function and selective impairment of Ran‐binding protein 2 (Ranbp2)

Mild Encephalopathy with Reversible Lesions in the Splenium of Corpus Callosum and Bilateral Cerebral Deep white Matter in Identical twins

Contact Info

Product

Resources

About