17 research outputs found
Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development
The development of the human cerebral cortex is a complex and dynamic process,
in which neural stem cell proliferation, neuronal migration, and post-migratory neuronal
organization need to occur in a well-organized fashion. Alterations at any of
these crucial stages can result in malformations of cortical development (MCDs),
a group of genetically heterogeneous neurodevelopmental disorders that present with
developmental delay, intellectual disability and epilepsy. Recent progress in genetic
technologies, such as next generation sequencing, most often focusing on all proteincoding exons (e.g., whole exome sequencing), allowed the discovery of more than a
100 genes associated with various types of MCDs. Although this has considerably
increased the diagnostic yield, most MCD cases remain unexplained. As Whole
Exome Sequencing investigates only a minor part of the human genome (1–2%),
it is likely that patients, in which no disease-causing mutation has been identified,
could harbor mutations in genomic regions beyond the exome. Even though functional
annotation of non-coding regions is still lagging behind that of protein-coding genes,
tremendous progress has been made in the field of gene regulation. One group
of non-coding regulatory regions are enhancers, which can be distantly located
upstream or downstream of genes and which can mediate temporal and tissue-specific
transcriptional control via long-distance interactions with promoter regions. Although
some examples exist in literature that link alterations of enhancers to genetic disorders, a
widespread appreciation of the putative roles of these sequences in MCDs is still lacking.
Here, we summarize the current state of knowledge on cis-regulatory regions and
discuss novel technologies such as massively-parallel reporter assay systems, CRISPRCas9-based screens and computational approaches that help to further elucidate the
emerging role of the non-coding genome in disease. Moreover, we discuss existing
literature on mutations or copy number alterations of regulatory regions involved in brain
development. We foresee that the future implementation of the knowledge obtained
through ongoing gene regulation studies will benefit patients and will provide an
explanation to part of the missing heritability of MCDs and other genetic disorders
The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1
First described in 1991, Yin Yang 1 (YY1) is a transcription factor that is ubiquitously
expressed throughout mammalian cells. It regulates both transcriptional activation and
repression, in a seemingly context-dependent manner. YY1 has a well-established role
in the development of the central nervous system, where it is involved in neurogenesis
and maintenance of homeostasis in the developing brain. In neurodevelopmental and
neurodegenerative disease, the crucial role of YY1 in cellular processes in the central
nervous system is further underscored. In this mini-review, we discuss the various
mechanisms leading to the transcriptional activating and repressing roles of YY1,
including its role as a traditional transcription factor, its interactions with cofactors and
chromatin modifiers, the role of YY1 in the non-coding genome and 3D chromatin
organization and the possible implications of the phase-separation mechanism on YY1
function. We provide examples on how these processes can be involved in normal
development and how alterations can lead to various diseases
Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.
Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies
Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.
Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function
Collateral for Loans from Norges Bank – Consequences of Changes in the Rules
Norges Bank requires collateral for all lending to banks. Collateral is provided in the form of securities which are pledged to Norges Bank. The list of eligible securities was changed in 2005. The aim of the changes has been to reduce Norges Bank’s risk while ensuring that the borrowing facilities available to banks remain sufficient for payments to be settled and monetary policy to be implemented effectively. This article presents the changes that have been made and analyses the effects on Norges Bank’s risk and banks’ borrowing facilities. We conclude that the changes in the rules have indeed reduced Norges Bank’s risk, and that the rules still provide for adequate borrowing facilities