• Case report
• Genome-wide association study
• Mediator complex
• Neurodevelopmental disorders
• Transcriptional regulation

• Humans
• Neurodevelopmental Disorders/genetics
• Neurodevelopmental Disorders/metabolism
• Mediator Complex/genetics
• Mediator Complex/metabolism
• Animals

• Brain
• Mediator complex
• Neurological diseases
• Personalized medicine
• Stroke

• Humans
• Cyclin-Dependent Kinase 8/genetics
• Cyclin-Dependent Kinase 8/metabolism
• Transcription Factors/metabolism
• Mutation
• Mediator Complex/genetics

• behavior phenotypes
• genetic modification
• intellectual disability
• mouse model

• Consanguinity
• MED17 mutation
• homozygosity
• intellectual disability

Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

• H2020 Marie Skłodowska-Curie Actions
• Erasmus Universiteit Rotterdam

• Charcot-Marie-Tooth (CMT) disease
• axonal transport deficiency
• cytoskeleton
• mitochondria
• neurodegeneration
• organelle transport

• R21 DC018237 NIDCD NIH HHS
• F32 GM137580 NIGMS NIH HHS
• P30 AG068635 NIA NIH HHS
• R01 AR069876 NIAMS NIH HHS
• P30 CA014195 NCI NIH HHS

• Basel-Vanagaite-Smirin-Yosef syndrome
• Intellectual disability
• MED25
• Multiple congenital anomalies
• Neuropathy
• Polymicrogyria
• Thin corpus callosum

• eRNA
• enhancer
• epigenetic
• gene regulation
• neuron
• transcription

• Animals
• Brain/growth & development
• Brain/metabolism
• Brain Diseases/genetics
• Brain Diseases/metabolism
• Enhancer Elements, Genetic
• Humans
• Neurogenesis

• DP1 DA039650 NIDA NIH HHS
• R00 DA034681 NIDA NIH HHS
• R01 MH114990 NIMH NIH HHS

• AARS
• CMT2N
• Localization
• Mutation
• Process growth
• Valproic acid

• Aggregate
• Binding
• Epigenetics
• GWAS
• Genetics
• Histone code
• Minimotif
• Posttranslational modification
• Trafficking

• R21 AI116411 NIAID NIH HHS
• R01 LM010101 NLM NIH HHS
• R01 GM079689 NIGMS NIH HHS
• P20 GM109025 NIGMS NIH HHS
• R01 MH109706 NIMH NIH HHS
• R01 MH101054 NIMH NIH HHS
• U54 GM104944 NIGMS NIH HHS
• R15 GM107983 NIGMS NIH HHS
• P20 GM121325 NIGMS NIH HHS

• Axonal autosomal recessive inheritance
• Charcot-Marie-Tooth disease
• GDAP1 gene mutations
• Intronic mutations
• Whole-exome sequencing

• Haploinsufficiency
• Intellectual disability
• MED13L

The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved α-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor. Mutations inside the α-crystallin domain have been shown to enhance the chaperone activity of HSPB1 and increase the binding to client proteins. However, the HSPB1-P182L mutation, located outside and downstream of the α-crystallin domain, behaves differently. This specific HSPB1 mutation results in a severe neuropathy phenotype affecting exclusively the motor neurons of the peripheral nervous system. We identified that the HSPB1-P182L mutant protein has a specifically increased interaction with the RNA binding protein poly(C)binding protein 1 (PCBP1) and results in a reduction of its translational repressive activity. RNA immunoprecipitation followed by RNA sequencing on mouse brain lead to the identification of PCBP1 mRNA targets. These targets contain larger 3′- and 5′-UTRs than average and are enriched in an RNA motif consisting of the CTCCTCCTCCTCC consensus sequence. Interestingly, next to the clear presence of neuronal transcripts among the identified PCBP1 targets we identified known genes associated with hereditary peripheral neuropathies and hereditary spastic paraplegias. We therefore conclude that HSPB1 can mediate translational repression through interaction with an RNA binding protein further supporting its role in neurodegenerative disease.

• Charcot-Marie-Tooth
• Distal Hereditary Motor Neuropathy
• HSPB1
• PCBP1
• RNA immunoprecipitation

• Choreiform movement
• Compound heterozygous mutation
• Mediator complex subunit 17
• Nystagmus
• Whole exome sequencing

• Brain/pathology
• Child
• Chorea/genetics
• Chorea/pathology
• Chorea/physiopathology
• DNA Mutational Analysis
• Exome
• Female
• Heterozygote
• Humans
• Magnetic Resonance Imaging
• Male
• Mediator Complex/genetics
• Mutation
• Phenotype
• Siblings

• ALS5/SPG11/KIAA1840 mutations
• Charcot–Marie–Tooth disease
• axonal degeneration
• spatacsin

Inherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications.

We designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN.

Genetic diagnosis was achieved in 137 patients (31 %) and involved 195 pathogenic variants in 31 genes. 93 patients had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with X-linked disease.

Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14).

Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks.

Our results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for IPN.

The online version of this article (doi:10.1186/s12881-015-0224-8) contains supplementary material, which is available to authorized users.

• MED23
• intellectual disability (ID)
• mediator complex
• whole exome sequencing (WES)

• Abnormalities, Multiple/diagnosis
• Abnormalities, Multiple/genetics
• Abnormalities, Multiple/pathology
• Child
• Child, Preschool
• Exome
• Gene Expression
• Heart Defects, Congenital/diagnosis
• Heart Defects, Congenital/genetics
• Heart Defects, Congenital/pathology
• Heterozygote
• High-Throughput Nucleotide Sequencing
• Humans
• Intellectual Disability/diagnosis
• Intellectual Disability/genetics
• Intellectual Disability/pathology
• Male
• Mediator Complex/genetics
• Mutation, Missense
• Proto-Oncogene Proteins c-fos/genetics
• Proto-Oncogene Proteins c-fos/metabolism
• Proto-Oncogene Proteins c-jun/genetics
• Proto-Oncogene Proteins c-jun/metabolism
• Siblings

• ZIA HG000215-07 Intramural NIH HHS

• Arabidopsis
• RNA polymerase II
• abiotic stress
• defense signaling
• development
• mediator complex
• rice
• transcription

• Clinical genetics
• Molecular genetics

• CMT
• Hereditary motor and sensory neuropathy
• Molecular genetics
• Molecular pathogenesis
• Myelin
• Neuromuscular disease therapeutics

• Humans
• Intrinsically Disordered Proteins/biosynthesis
• Intrinsically Disordered Proteins/chemistry
• Nuclear Pore Complex Proteins/biosynthesis
• Nuclear Pore Complex Proteins/chemistry
• Protein Unfolding
• Ribonucleoproteins/biosynthesis
• Ribonucleoproteins/chemistry

• R01 GM063004 NIGMS NIH HHS
• U54 CA143869 NCI NIH HHS
• U54 GM105816 NIGMS NIH HHS
• U54GM105816 NIGMS NIH HHS

This review summarizes the current understanding of the role of nuclear bodies in regulating gene expression. The compartmentalization of cellular processes, such as ribosome biogenesis, RNA processing, cellular response to stress, transcription, modification and assembly of spliceosomal snRNPs, histone gene synthesis and nuclear RNA retention, has significant implications for gene regulation. These functional nuclear domains include the nucleolus, nuclear speckle, nuclear stress body, transcription factory, Cajal body, Gemini of Cajal body, histone locus body and paraspeckle. We herein review the roles of nuclear bodies in regulating gene expression and their relation to human health and disease.

• gene expression
• genome organization
• nuclear bodies
• transcription

• R03 DK062174 NIDDK NIH HHS
• R21 DK065725 NIDDK NIH HHS

• Cell fate
• Disease
• Lineage development
• Mediator complex
• Transcription

Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is the most common inherited neuromuscular disorder affecting at least 1 in 2500. CMT disease is pathologically and genetically heterogeneous and is characterized by a variable age of onset, slowly progressive weakness and muscle atrophy, starting in the lower limbs and subsequently affecting the upper extremities. Symptoms are usually slowly progressive, especially for the classic and late-onset phenotypes, but can be rather severe in early-onset forms. CMT is grouped into demyelinating, axonal and intermediate forms, based on electrophysiological and pathological findings. The demyelinating types are characterized by severely reduced motor nerve conduction velocities (MNCVs) and mainly by myelin abnormalities. The axonal types are characterized by normal or slightly reduced MNCVs and mainly axonal abnormalities. The intermediate types are characterized by MNCVs between 25 m/s and 45 m/s and they have features of both demyelination and axonopathy. Inheritance can be autosomal dominant, X-linked, or autosomal recessive. Mutations in more than 30 genes have been associated with the different forms of CMT, leading to major advancements in molecular diagnostics of the disease, as well as in the understanding of pathogenetic mechanisms. This editorial aims to provide an account that is practicable and efficient on the current molecular diagnostic procedures for CMT, in correlation with the clinical, pathological and electrophysiological findings. The most frequent causative mutations of CMT will also be outlined.

• Charcot-Marie-Tooth disease
• Charcot-Marie-Tooth
• Neuropathy
• Genetics
• Molecular diagnosis

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. The risk factors for CVD include environmental and genetic components. Human mutations in genes involved in most aspects of cardiovascular function have been identified, many of which are involved in transcriptional regulation. The Mediator complex serves as a pivotal transcriptional regulator that functions to integrate diverse cellular signals by multiple mechanisms including recruiting RNA polymerase II, chromatin modifying proteins and non-coding RNAs to promoters in a context dependent manner. This review discusses components of the Mediator complex and the contribution of the Mediator complex to normal and pathological cardiac development and function. Enhanced understanding of the role of this core transcriptional regulatory complex in the heart will help us gain further insights into CVD.

• Animals
• Disease/genetics
• Gene Expression Regulation
• Gene Regulatory Networks
• Humans
• Neoplasms/genetics
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• Transcription, Genetic

• R01 CA146445 NCI NIH HHS
• R01 HG002668 NHGRI NIH HHS
• CA146445 NCI NIH HHS
• HG002668 NHGRI NIH HHS

• AR-HMSN
• CMT4
• X-linked CMT
• autosomal recessive hereditary motor neuropathy AR-HMN
• axonal recessive Charcot–Marie–Tooth disease AR-CMT
• demyelinating recessive Charcot-Marie-Tooth disease
• demyelinating recessive hereditary motor and sensory neuropathy

• Animals
• Chromosome Aberrations
• Genes, Recessive
• Hereditary Sensory and Autonomic Neuropathies/classification
• Hereditary Sensory and Autonomic Neuropathies/diagnosis
• Hereditary Sensory and Autonomic Neuropathies/genetics
• Humans
• Multigene Family/genetics

• Dejerine–Sottas neuropathy
• congenital hypomyelinating neuropathy
• congenital syndromal disorders
• hereditary metabolic diseases
• hereditary neuropathies
• spinal muscular atrophy

• Age of Onset
• Hereditary Sensory and Autonomic Neuropathies/diagnosis
• Hereditary Sensory and Autonomic Neuropathies/genetics
• Hereditary Sensory and Autonomic Neuropathies/physiopathology
• Humans
• Membrane Proteins/genetics
• Mutation/genetics
• Phenotype
• S100 Calcium Binding Protein beta Subunit

• Charcot−Marie−Tooth disease (CMT)
• DNA
• genetic counseling
• genetic testing
• hereditary motor and sensory neuropathy (HMSN)
• hereditary motor neuropathy (HMN)
• hereditary sensory and autonomic neuropathy (HSAN)
• multiplex ligation-dependent probe amplification (MLPA)
• polymerase chain reaction (PCR)

• Charcot-Marie-Tooth disease
• Medical genetics
• Next-generation sequencing

• Charcot-Marie-Tooth disease
• Medical genetics
• Next-generation sequencing

Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese.

Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%).

This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.

• Adolescent
• Adult
• Amino Acid Sequence
• Animals
• Asian People/ethnology
• Asian People/genetics
• Base Sequence
• Cattle
• Charcot-Marie-Tooth Disease/genetics
• Child
• Child, Preschool
• Cohort Studies
• DNA Mutational Analysis
• Ethnicity/genetics
• Female
• Humans
• Male
• Mice
• Middle Aged
• Molecular Sequence Data
• Mutation
• Rats
• Taiwan
• Young Adult