bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plant Cell Division
Authors: Müller Sabine 
Published: April 2013

AbstractCell division is characterised by the segregation of genetic material and the redistribution of cellular contents facilitated by the cytoskeleton. Plant cells derive from divisions in the meristems of developing organs. However, plant cells are enclosed in rigid cell walls, unable to migrate and change their location within tissues. Thus, positions of division planes, together with successive polarised cell expansion are the major determinants of cell shape and consequently morphology of plants. The basic building blocks of the cytoskeleton, tubulins, actins and cytoskeleton associated motor‐ and nonmotor‐proteins are conserved. Yet, plants have developed unique cytoskeletal arrays and molecular mechanism to determine the division plane very early in mitosis and to facilitate the synthesis and insertion of the partitioning cell plate at the end of cell division.Key Concepts:Plant cells utilise specialised cytoskeletal arrays to determine the division plane early in mitosis and form a cell plate to separate daughter cells late in mitosis.Cell geometry and nuclear position are informative for division plane selection.The preprophase band (PPB) predicts the future division plane and recruits proteins that identify the cortical division site (CDS) throughout mitosis.Mutants defective in PPB or CDS establishment/maintenance exhibit mispositioned cell walls and altered cell and plant morphology.Successful cell plate formation relies on cytoskeletal reorganisation and vesicle fusion.
Genetics of Silver–Russell Syndrome
Authors: Eggermann Thomas 
Published: April 2013

Abstract

Human growth is a complex process and requires the appropriate interaction of many factors. Central members in the growth axes are regulated epigenetically and thereby reflect the profound significance of imprinting for correct mammalian ontogenesis. A prominent imprinting disorder associated with a disturbed imprinting is Silver–Russell syndrome (SRS), a congenital disease characterised by intrauterine and post‐natal growth retardation and further characteristic features. SRS is molecularly heterogenous: 7% of patients carry a maternal uniparental disomy of chromosome 7, >38% show a hypomethylation in the imprinting control region 1 in 11p15. Interestingly, hypermethylation of the same region is associated with the overgrowth disease Beckwith–Wiedemann syndrome (BWS), thus SRS and BWS can be regarded as genetically (and clinically) opposite diseases. Because of the different imprinting regions involved, SRS is a suitable model to decipher the role of imprinting in growth and the functional interaction between imprinted genes in different genomic regions.

Key Concepts:

Silver–Russell syndrome is a clinically heterogeneous syndrome and belongs to the group of congenital imprinting disorders.

Congential imprinting disorders show a broad spectrum of epimutations and mutations in differentially methylated regions.

Different chromosomal regions might be affected by molecular alterations in Silver–Russell syndrome, that is chromosomes 7 and 11p15.

The functional significance of the observed molecular aberrations in SRS is currently unknown.

Multilocus methylation defects are present in a considerable number of patients with imprinting disorders and indicate a general disturbance of the establishment and/or maintenance of imprinting marks.

Deciphering the molecular and functional basis for the clinical course of SRS helps to generally understand epigenetic regulation.
Molecular Genetics of Kabuki Syndrome
Authors: Micale Lucia , Merla Giuseppe 
Published: April 2013

Abstract

Kabuki syndrome (KS) is a rare, multiple congenital anomalies/mental retardation syndrome characterised by a peculiar face, skeletal abnormalities, cardiac anomalies, and immunological defects. Exome sequencing identified
MLL2
mutations as a major cause of KS. MLL2 is a member of the Mixed Lineage Leukaemia (MLL) family of histone methyltransferases, essential in the epigenetic control of active chromatin states. MLLs act as transcriptional co‐activators in embryogenesis and development. As a significant proportion of patients do not have any
MLL2
mutation, the existence of additional genes associated with this syndrome was postulated. By Comparative Genomic Hybridisation (CGH) array,

de novo

partial and/or complete deletions of
KDM6A
gene have been identified in a small group of
MLL2
‐mutation‐negative Kabuki patients. Notably,
KDM6A
codes a histone demethylase that interacts with MLL2. Overall, these findings suggest that Kabuki syndrome is a genetic heterogeneity disease and highlights the growing role of histone methylases and histone demethylases in multiple congenital anomalies and intellectual‐disability syndromes.

Key Concepts:

Kabuki syndrome is a rare, multiple malformation disorder characterised by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability.

Kabuki syndrome is an autosomal dominant condition that

de novo

arises in the majority of patients. It is phenotypically variable and genetically heterogeneous.

Whole exome sequencing identified mutations in
MLL2
gene in approximately 70% of the Kabuki patients.

The
MLL2
gene encodes a multiple domain‐containing protein that methylates the Lys‐4 position of histone H3 (H3K4), an epigenetic mark correlated with transcriptional active chromatin.

Approximately 70% of
MLL2
mutation‐positive KS patients carry truncating mutations predicted to result in haploinsufficiency or nonfunctional MLL2 protein.

In a search for an additional gene causing Kabuki syndrome, microdeletions of the
KDM6A
gene were identified in three
MLL2
‐mutation‐negative Kabuki patients.

KDM6A is a histone demethylases that interacts with MLL2.

Histone methylases and histone demethylases are key‐genes involved in multiple congenital anomalies and intellectual‐disability syndromes.
Germline Copy Number Variation and Cancer Risk
Authors: de Voer Richarda M , Venkatachalam Ramprasath , van Kessel Ad Geurts , Kuiper Roland P 
Published: April 2013

Abstract

Cancer is usually considered to be an acquired disease caused by the progressive accumulation of somatic
deoxyribonucleic acid (DNA)
changes. It is clear, however, that inherited factors may also play a significant role in the initiation of this disease. Some of these factors represent loss‐of‐function mutations in tumour suppressor genes, resulting in an increased cancer risk among carriers. Such an increased risk may also be attributed to the presence of multiple polymorphic variants such as single nucleotide polymorphisms (SNPs), each of which may convey a mild effect upon cancer susceptibility. DNA copy number variation (CNV) and other structural variations in the human genome are increasingly recognised as an alternative source of genetic variation that may influence cancer risk. Specifically, rare CNVs may affect important cancer‐associated genes and/or pathways and, thus, provide an explanation for moderate‐ to high‐risk cancer families. Therefore, it is anticipated that the identification of rare germline CNVs in unexplained familial and early onset cancer patients will contribute to our understanding of cancer predisposition and development.

Key Concepts:

Copy number variation (CNV) is a common form of normal variation affecting a significant proportion of the human genome.

CNVs frequently encompass annotated genes.

Disruption and/or silencing of critical genes located in rare CNVs may result in increased risk of disease, including cancer.

Genome‐wide copy number analysis can be used as a strategy to identify novel moderate‐ to high‐penetrant cancer predisposing genes and/or mechanisms.

Discovery of cancer‐predisposing CNVs may reveal new cancer syndromes that exhibit additional clinical features.
Molecular Genetic Basis of Myotonic Dystrophy
Authors: Radvanszky Jan , Kadasi Ludevit 
Published: April 2013

Abstract

Myotonic dystrophy (DM) comprises at least two genetically distinct forms, both of which are caused by expansions of microsatellite repeats. Expansion of a CTG repeat in the
DMPK
gene leads to DM1, whereas expansion of a CCTG repeat in the
ZNF9
gene causes DM2. In both cases, the repeat units may expand to several thousand repeats. Strikingly similar phenotypes, mutation types and pathological findings suggest a common pathogenic mechanism for both DM1 and DM2. However, the differences between DM1 and DM2 may be a consequence of locus‐specific effects involving haploinsufficiency of different genes and downstream events triggered by CUG or CCUG transcripts. Altogether, the complex DM1 and DM2 phenotypes are probably caused by specific combinations of several possible pathogenic pathways in different tissues of individual patients.

Key Concepts:

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are complex multisystemic disorders with highly similar but not identical symptoms.

Both DM1 and DM2 are caused by expansions of microsatellite repeats, however, in two distinct genes (
DMPK
and
ZNF9
).

Mechanisms leading to the DM1 and DM2 symptoms are very complex with several possible pathogenic pathways.

The best described pathogenic pathway involves the misregulation of two alternative splicing regulators, CUG‐BP1 (gain of function) and MBNL1 (loss of function), leading to target‐specific splicing alterations.

Both CUG‐BP1 and MBNL1 are multifunctional proteins; thus, their activation/sequestration have effect on further cellular functions such as transcription, translation and mRNA decay.

Both DM1 and DM2 causing expansions can also lead to decreased levels of proteins coded by genes around and near to the expansion sites, such as
DMPK
,
ZNF9
,
SIX5
and
DMWD.

The exact molecular pathogenic mechanism in certain tissues is probably not uniform, it rather represents a specific combination of several distinct pathogenic pathways.
Implications ofRNA‐binding Proteins for Human Diseases
Authors: Lukong Kiven E , Fatimy Rachid El 
Published: April 2013

AbstractRNA‐binding proteins play pivotal roles inribonucleic acid (RNA)metabolism. The identification of mRNA targets of RNA‐binding proteins has also contributed to the delineation function of these proteins. The different tissue specificity and subcellular localisation of the RNA‐binding proteins show that these proteins can regulate specific aspects of mRNA processing and function in cells, from splicing and transport to translation and stability. Mutations, deletions and/or autoimmune reactions affecting RNA‐binding proteins lead to alterations in cellular processes, normal development and various disorders. The vast majority of these diseases are neurological or neuromuscular disorders and includes myotonic dystrophy, spinal muscular atrophy, oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, fragile X syndrome, fragile X associated tremor/ataxia syndrome and paraneoplastic opsoclonus‐myoclonus ataxia. Altered expression of RNA‐binding proteins is also a common feature in various cancers. Understanding the molecular mechanisms of RNA‐binding proteins aberrations in disease could lead to better‐targeted therapies.Key Concepts:RNA‐binding proteins are key components in RNA metabolism.RNA‐binding proteins contain modular amino acid sequences that mediate RNA binding.The two largest RBP families contain the RNA recognition motif (RRM) and the K homology (KH) domains.Deleterious RNA‐dominant loss‐of‐function or gain‐of‐function mechanisms are associated with defects in RBPs.Several neurological and neuro‐muscular diseases are linked to defects in RBPs.FXS is caused by CGG repeat in the 5′ untranslated region of theFMR1gene.Antibodies against RBPs Hu and Nova are implicated in the pathogenesis of paraneoplastic neurologic syndromes.DM1 is associated with the accumulation of RNA aggregates and misregulation of the RBPs, MBNL1 and CUGBP1.Translocations of genes encoding RBPs and aberrant expression RBPs have been associated with various cancers.
Molecular Genetics of Myelodysplastic Syndromes
Authors: Bejar Rafael , Steensma David P 
Published: April 2013

AbstractMyelodysplastic syndromes (MDS) are a group of clonal haematopoietic disorders characterised clinically by inefficient haematopoiesis, cytopenias of the peripheral blood and a risk of progression to acute myeloid leukaemia (AML). Molecularly, MDS can be associated with a wide range of acquired chromosomal abnormalities, epigenetic alterations and single gene mutations. These abnormalities affect diverse molecular pathways includingribonucleic acid(RNA) splicing machinery, epigenetic modifiers, haematopoietic transcription factors, receptor tyrosine kinase signalling, cell cycle regulation and apoptosis. The particular combination of somatic genetic lesions in any given patient will influence how their disease is manifested, and together with individual background germline genotype may explain much of the clinical heterogeneity associated with MDS. Here, the common genetic abnormalities that underlie MDS and how these abnormalities influence the development and progression of these disorders have been reviewed.Key Concepts:MDS represent a collection of disorders marked by abnormal, inefficient haematopoiesis, cytopenias of the peripheral blood and a predisposition for progression to AML.Like other haematopoietic malignancies, MDS arise from the clonal expansion of a single, abnormal haematopoietic cell.The abnormal MDS cells that maintain the disease have the ability to self‐renew and clonally expand because they have a selective growth advantage compared to their normal counterparts.Impaired haematopoietic differentiation in MDS can lead to cytopenias or to the production of terminally differentiated cells with abnormal function.A combination of somatic genetic abnormalities (acquired changes to thedeoxyribonucleic acid(DNA) coding sequence), epigenetic abnormalities (heritable changes in gene expression) and marrow microenvironmental abnormalities contribute to the development and progression of MDS.Approximately, 50% of MDS cells have a chromosomal abnormality detectable by routine metaphase karyotype analysis.More than 75% of patients have acquired mutations in one or more genes known to be recurrently altered in MDS.Recurrent mutations in MDS implicate several molecular pathways in the development and progression of disease including; altered RNA splicing mechanisms, epigenetic changes in DNA methylation and histone modifications, activation of growth factor signalling cascades, impaired differentiation and abnormal regulation of cell cycle and apoptosis.Acquired mutations in several MDS genes have prognostic significance that is independent of clinically based prognostic scoring systems.Chromosomal abnormalities and mutations in some genes can predict response to specific therapies used to treat patients with MDS.
Genetics of Susceptibility to Mycobacterial Disease
Authors: Selvaraj Paramasivam , Alagarasu Kalichamy , Raghavan Sampathkumar 
Published: April 2013

Abstract

The genus Mycobacteria contains important pathogens of humans including

Mycobacterium tuberculosis

and

Mycobacterium leprae

. The outcome of mycobacterial infection is influenced by variations in human genes. Genetic susceptibility to mycobacteria involves multiple genes that contribute to the innate immune recognition of mycobacteria (genes coding for pattern recognition receptors), recognition of mycobacteria by the adaptive immune system involving products of human leucocyte antigen/major histocompatibility complex genes and effector responses of the immune system (genes affecting cytokines, chemokines and immunomodulators). Host genetic susceptibility to pathogens is complicated by the genetics of pathogen, gene‐environment and gene–gene interactions. Moreover, ethnicity specific effects further add fuel to the complication. A series of concerted comprehensive immunogenetic studies are warranted to decipher new molecular players and delineate complex host–pathogen interactions. This might identify the genetic factors that are definitely associated with mycobacterial diseases and could lead to development of novel therapeutics and prophylaxis. Convergence of immunogenomics, pharmacogenomics and vaccinomics could yield better tools to tackle these dreadful diseases of mankind.

Key Concepts:

Outcome of a mycobacterial infection depends on gender, age, HIV infection status, malnutrition, BCG vaccination, host immune responses, pathogen variation and host genetics, which varies according to ethnicity.

Extensive studies have implicated the role of alleles from human leucocyte antigen (HLA) genes/major histocompatibility complex (MHC) genes and single nucleotide polymorphisms (SNPs) of various non‐HLA genes/non‐MHC genes in conferring susceptibility to mycobacterial disease.

Polymorphisms in the genes coding for pattern recognition receptors such as toll‐like receptors, mannose‐binding lectins, mannose receptors, surfactant proteins and DC‐SIGN affect susceptibility to mycobacterial disease.

HLA‐DRB1
*
15 and HLA‐DQB1 alleles having aspartic acid at β57 have been shown to be associated with TB in many populations.

SNPs in the genes coding for
IFNG
,
IL10
,
CCL2
, vitamin D receptor,
NOS2A
and other effector molecules influence susceptibility to mycobacterial disease.

SNPs in the genes coding for immune mediators could predict response to treatment.

Ethnicity specific effects, and strain variation in the pathogen, gene–gene and gene–environment interactions affect genetic susceptibility.
Genetics of Chromosome 22q11.2 Deletion Syndrome
Authors: Fernández Luis 
Published: April 2013

Abstract

The 22q11.2 deletion syndrome is the most frequent deletion syndrome in humans. The genomic architecture of this chromosomal region makes it prone to anomalous meiotic rearrangements causing the loss of genetic material in the parental gamete. Gene dosage‐dependent embryonic developmental processes are subsequently disrupted and lead to multiple birth malformations, the severity of which is modulated by other unknown genetic and environmental factors. The resulting clinical picture is a heterogeneous phenotype with no correlation with the genetic lesion. Currently, genetic diagnosis is mostly performed by gene dosage quantification techniques targeting region 22q11.2, but the recent development of whole‐genome scanning methods enabling a full molecular characterisation of patients under uniform criteria and a better genotype–phenotype correlation will help to understand the pathogenesis of this disorder.

Key Concepts:

The 22q11.2 deletion syndrome is the most common human microdeletion syndrome.

It usually occurs
de novo
, although an estimated 10% of cases are inherited.

LCR22s are homologous DNA sequences that spontaneously mediate the deletion process during meiosis.

Parents should be studied both genomically and cytogenetically to rule out carrier status or occasional balanced rearrangements.

Phenotypic variability is likely to be due to genetic and environmental factors during development, and it hampers a genotype–phenotype correlation.

Genomic techniques will contribute to a better genotypic characterisation and understanding of the disease.
Technological Advances in the Detection of Novel Fusion Genes
Authors: Leow Pay Chin , Ku Chee‐Seng , Soo Ross , Soong Richie 
Published: April 2013

Abstract

Since their first discovery in chronic myeloid leukaemia, fusion genes have been shown to play a central role in haematologic cancers. However, aberrations arising from this type of somatic mutations have been neglected in common solid tumours, largely because of limitations of current cytogenetic techniques. The recent discovery of recurrent gene fusions in prostate and lung cancer has led to a renewed interest in the identification of novel fusion genes in solid tumours. In this review, we discuss the technical challenges of studying gene fusions in solid tumours, appraise the application of newer molecular techniques and highlight emerging technologies, with the focus on next‐generation sequencing and chromogenic
in situ
hybridisation, that have greatly enhanced the speed and reliability of gene fusion discovery in malignant solid tumours.

Key Concepts:

A fusion gene is a gene hybrid formed from linking two physically separated genes.

A fusion gene can occur as a result of chromosomal rearrangements such as translocations, insertions, deletions and inversions, which lead to novel protein fusion products.

The detection of fusion genes is being recognised as a promising clinical tool for the diagnosis, staging classification, prognosis and treatment of cancer.

Gene fusions have been an underappreciated class of mutation in solid tumours.

The identification of gene fusions in solid tumours is technically challenging due to the complex and often chaotic karyotypic profiles of solid cancers.

Recent advances in genomics obtained from next generation sequencing, coupled with the emerging field of bioinformatics and ever‐advancing molecular techniques, have uncovered many novel oncogenic fusion genes in solid tumours that were unable to be detected by traditional cytogenetic methods.

Fluorescence
In‐Situ
Hybridisation (FISH) is recognised as the most effective diagnostic methods for the detection of gene fusions.

Transcriptome‐sequencing (also known as RNA‐sequencing), a recently introduced high‐throughput method of characterising ribonucleic acid (RNA) transcribed from the genome is rapidly emerging as the key method for the discovery of gene fusions.

Numerous challenges and unanswered issues remained with the discovery of novel gene fusions and their development as effective targeted cancer therapies or as clinical diagnostic and/or prognostic tools.
Syphilis: Epidemiological Aspects
Authors: Wright David J , Norris Steven J , Dhillon Rishi H‐P , Edmondson Diane G 
Published: April 2013

AbstractSyphilis continues to represent a significant public health issue. The number of cases globally remains high at over ten million newly infected patients each year, with highest rates seen in countries of low income. The main mode of transmission is by sexual contact, with men who have sex with men, co‐infection with human immunodeficiency virus (HIV) and the sexually promiscuous particularly at risk. Infection rates are also linked with times of war and social upheaval; this is also true of other sexually transmitted diseases.Prevention of new cases is clearly desirable. Most major health organisations (including the CDC and WHO) have elimination plans which rely on education, promotion of safe sexual practices and screening of high‐risk individuals at the core of the strategy.Key Concepts:Clinical differences in the treponematoses have been attributed to adaptation of the organism to climatic factors.An African rather than an American origin is suggested for syphilis.The control of syphilis by public health measures is exemplified by a lower incidence of syphilis in Europe and North America than the rest of the world.An increased incidence in syphilis is found associated with wars and civil disturbance.