Neuronal Autophagy and  Neurodevelopmental Disorders

Lee, Kyung Min; Hwang, Sung‐Wook; Lee, Jin A

doi:10.5607/en.2013.22.3.133

Cited by 94 publications

(76 citation statements)

References 74 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, a proportion of fibroblasts from affected individuals but not control subjects immunostain positive for p62 in a granular pattern ( Figure S7), which might suggest a defect in the autophagy pathway, as seen in many neurodegenerative and neurodevelopmental disorders. 48 Interestingly, cultured fibroblasts from individuals with MSS similarly contain numerous cytoplasmic electron-dense, sometimes multilamellar inclusion, bodies in both individuals with and without SIL1 mutations. 1 MSS and the SNX14 phenotype share the presence of ID, cerebellar atrophy, hypotonia, and ataxia.…”

Section: Skeleton and Limbsmentioning

confidence: 94%

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Thomas¹,

Hj²,

Setó‐Salvia³

et al. 2014

The American Journal of Human Genetics

View full text Add to dashboard Cite

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.

show abstract

Section: Skeleton and Limbsmentioning

confidence: 94%

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Thomas¹,

Hj²,

Setó‐Salvia³

et al. 2014

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…Defects in lysosomal function and autophagy have been linked to neurodevelopmental and neurodegenerative disorders (48). Disruption of a RAD6-KCMF1-UBR4 complex via RAD6A mutations (such as R7W and R11Q) could thus lead to a buildup of toxic proteins and/or organelles to negatively affect neuronal function in XLID patients.…”

Section: Rad6 Ap-ms Identifies a Set Of Novelmentioning

confidence: 99%

KCMF1 (potassium channel modulatory factor 1) Links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and Lysosome-Mediated Degradation*

Hong

Kaustov

Coyaud

et al. 2015

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

RAD6 is a ubiquitin E2 protein with roles in a number of different biological processes. Here, using affinity purification coupled with mass spectrometry, we identify a number of new RAD6 binding partners, including the poorly characterized ubiquitin E3 ligases KCMF1 (potassium channel modulatory factor 1) and UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4), a protein that can bind N-end rule substrates, and which was recently linked to lysosome-mediated degradation and autophagy. NMR, combined with in vivo and in vitro interaction mapping, demonstrate that the KCMF1 C terminus binds directly to RAD6, whereas N-terminal domains interact with UBR4 and other intracellular vesicle-and mitochondriaassociated proteins. KCMF1 and RAD6 colocalize at late endosomes and lysosomes, and cells disrupted for KCMF1 or RAD6 function display defects in late endosome vesicle dynamics. Notably, we also find that two different RAD6A point mutants (R7W and R11Q) found in X-linked intellectual disability (XLID) patients specifically lose the interaction with KCMF1 and UBR4, but not with other previously identified RAD6 interactors. We propose that RAD6-KCMF1-UBR4 represents a unique new E2-E3 complex that targets unknown N-end rule substrates for lysosome-mediated degradation, and that disruption of this complex via RAD6A mutations could negatively affect neuronal function in XLID patients. RAD6 is a ubiquitin E2 conjugating protein that plays a number of important roles in eukaryotes, including histone H2B ubiquitylation, postreplication DNA damage repair and degradation of proteins via the N-end rule pathway (1, 2). This wide variety of functions is mediated via interactions with at least five different ubiquitin E3 ligases, which target the multipurpose E2 to a diverse array of substrates.In mammals, RAD6 is encoded by two genes, UBE2A (the protein product of this gene has historically been referred to as RAD6A) and UBE2B (RAD6B). The human UBE2A gene is located on the X chromosome (Xq24) and the UBE2B locus maps to 5q31.1 (3). The human RAD6 proteins share ϳ95% identity at the amino acid level (supplemental Fig. S1), and the two variants appear to play redundant roles in processes such as DNA damage repair (4). Both RAD6A and RAD6B are present in all tissues and cell lines examined (albeit at varying ratios), with highest mRNA levels measured in heart, testis, and brain (5).Previous reports have identified a variety of UBE2A coding sequence mutations in X-linked intellectual disability (XLID) 1 patients (6 -10), and a recent study revealed that human and Drosophila cells deficient for RAD6 function display defects in mitochondrial turnover and vesicle dynamics (6). However, the consequences of the XLID RAD6A mutations at the molecular level have not been well characterized, and the proteins that couple RAD6 to these new functions had not been identified.Here, we used an unbiased AP-MS (affinity purification coupled with mass spectrometry) approach to identify RAD6 interacting partners in human cells. Interestingly, we ...

show abstract

“…So much so, that it is likely that if they had been first discovered by neuroscientists, they would be universally called neurokines (50). Similar arguments apply to the regulation of mTOR mediated autophagy processes which might have been labeled as synaptic pruning functions if first discovered in the CNS (51). From this perspective, many of the genes implicated in ASD have both a synaptic or neuronal connectivity function and an immunological function.…”

Section: High Throughput Large-scale Data For Integrative Characterizmentioning

confidence: 79%

An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders

Kohane

2015

Biological Psychiatry

View full text Add to dashboard Cite

Analysis of large-scale systems of biomedical data provides a perspective on neuropsychiatric disease that may be otherwise elusive. Described here is an analysis of three large-scale systems of data from using Autism Spectrum Disorder (ASD) and ASD research as exemplar of what might be achieved from study of such data. The first is the biomedical literature that highlights that there are two very successful but quite separate research communities and findings pertaining to genetics and the molecular biology of ASD. That is those studies positing ASD etiologies related to immunological dysregulation and those related to disorders of synaptic function and neuronal connectivity. The second is the emerging use of electronic health record systems and other large clinical databases to allow the data acquired during the course of care to be used to identify distinct subpopulations, clinical trajectories and pathophysiological substructure of ASD. These reveal subsets of patients with distinct clinical trajectories some of which are immunologically related and others which follow pathologies conventionally thought of as neurological. The third is genome-wide genomic and transcriptomic analyses which show molecular pathways that overlap neurological and immunological mechanisms. The convergence of these three large-scale data perspectives illustrates the scientific leverage that large-scale data analyses can provide in guiding researchers in an approach to the diagnosis of neuropsychiatric disease that is inclusive and comprehensive.

show abstract

Neuronal Autophagy and Neurodevelopmental Disorders

Cited by 94 publications

References 74 publications

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

KCMF1 (potassium channel modulatory factor 1) Links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and Lysosome-Mediated Degradation*

An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders

Contact Info

Product

Resources

About