bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetics of Glomerular Basement Membrane Disorders
Authors: Kashtan Clifford E 
Published: April 2013

AbstractThe purpose of this review is to provide current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the glomerular basement membrane (GBM) (Alport syndrome (AS), thin basement membrane nephropathy (TBMN), hereditary angiopathy associated with nephropathy, aneurysms and muscle cramps (HANAC) syndrome and Pierson syndrome), as well as disorders involving genetic defects in cellular proteins that result in structural defects in GBMs (MYH9‐related disorders, Nail–Patella syndrome, NPS). All cases of AS and approximately 50% of cases of TBMN arise from mutations affecting a type IV collagen network composed of alpha;3, α4 and α5 type IV collagen chains. The cardinal clinical feature of these disorders is hematuria. HANAC syndrome is caused by mutations that affect type IV collagen networks made up of α1 and α2 type IV collagen chains and also presents with hematuria. In contrast, Pierson syndrome, which results from mutations in the gene encoding β2 laminin, is associated with proteinuria.Key Concepts:Important physiologic qualities of the glomerular capillary wall, such as high water flux and restricted transit of proteins, rely on specific extracellular matrix proteins and their interactions with other proteins and glomerular cells.Alport syndrome and thin basement membrane nephropathy (TBMN), the major genetic disorders of glomerular basement membranes (GBM), arise from abnormalities in a type IV collagen network comprising heterotrimers of α3, α4 and α5 type IV collagen chains.Extrarenal features of Alport syndrome (sensorineural deafness and ocular lesions) result from abnormal type IV collagen composition of cochlear and ocular basement membranes.Other inherited disorders of glomerular basement membranes result from laminin mutations (Pierson syndrome), mutations affected cytoskeletal function (MYH9‐related disorders) or dysregulation of the synthesis of extracellular matrix proteins (nail‐patella syndrome).
Genetics of
SHOX
Deficiency
Authors: Funari Mariana FA , Nishi Mirian Y , Scalco Renata C , Jorge Alexander AL 
Published: April 2013

Abstract

Isolated heterozygous

SHOX

defects are the most frequent monogenic cause of short stature, being associated with several phenotypes ranging from idiopathic short stature (ISS) without any specific features to Léri–Weill dyschondrosteosis.

SHOX

deficiency is also accountable for some clinical findings detected in Turner syndrome.

SHOX

gene is highly expressed in osteogenic cells and encodes a transcription factor, which is essential for bone development and growth. Molecular analysis of

SHOX

is essential as it can identify the aetiology of short stature, enables early diagnosis in other family members, allows genetic counselling and also supports the use of rhGH therapy in affected children. Even 14 years after the discovery of

SHOX

, and countless published studies, little is known about the real function of this gene and the mechanisms underlying

SHOX

‐related disorders. Further investigations will be essential for better understanding the exact role of this gene in the biological growth process.

Key Concepts:

Isolated
SHOX
gene defects are the most frequent monogenic cause of short stature.

SHOX
gene encodes a transcriptional activator, which is a member of the paired‐like homeodomain proteins.

SHOX
is predominantly expressed in osteogenic cells and is essential for bone development and growth.

The loss of one active allele leads to growth deficit, resulting in a wide spectrum of short stature phenotypes, including Léri–Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS) with no specific skeletal features.

The molecular analysis of
SHOX
gene elucidates the aetiology of short stature, enables genetic counselling and supports the use of recombinant growth hormone treatment.

Heterozygous
SHOX
mutations are identified in approximately 50–90% of patients with LWD.

Approximately 2–15% of patients with ISS have
SHOX
defects.

Deletions are responsible for approximately 80% of
SHOX
haploinsufficiency.

Longitudinal follow‐up studies of children with
SHOX
defects suggest a relatively well‐preserved prepubertal growth followed by compromised pubertal growth due to premature growth plate fusion.

Recombinant human growth hormone therapy improves growth velocity and final height in prepubertal patients with isolated
SHOX
haploinsufficiency.
Genetics of Susceptibility to Sporadic Ovarian Cancer
Authors: Katabathina Venkata S , Prasad Srinivasa R 
Published: April 2013

AbstractSpecific abnormalities involvingTP53, BRCA 1, BRCA 2, KRAS, BRAF, ERBB2, PIK3CA, PTEN, CTNNB1andARID1Agenes are responsible for the development of sporadic ovarian epithelial carcinoma (OEC). Recent advances in the field of cytogenetics and molecular biology have led to the development of an innovative classification of OEC that integrates the anatomical, clinical findings with molecular abnormalities and helps in prognostification and assessment of treatment response.TP53andBRCA 1andBRCA 2gene mutations are associated with high‐grade serous and high‐grade endometrioid subtypes andKRAS, BRAF, ERBB2, PIK3CA, PTEN, CTNNB1andARID1Aalterations are responsible for the development of low‐grade serous, low‐grade endometrioid, clear cell and mucinous subtypes of OEC. Tumours withTP53mutations uniformly carry a worse prognosis and the presence ofBRCA 1and2mutations predicts the positive treatment response to platinum compounds and Polyadenosine diphospahate(ADP) ribose polymerase (PARP) inhibitors. Evolving knowledge regarding the role of different genetic abnormalities in the oncogenesis of sporadic OEC may lead to the identification of ‘small molecules’ that can be used in the discovery of new drugs as well as biomarkers for screening, prognosis, and therapeutic response in the near future.Key Concepts:Ovarian epithelial carcinoma is categorised into two subgroups designated type 1 and type 2, which differ significantly in the pathogenesis, clinic‐biologic behaviour, and prognoses.Type 1 tumours are genetically stable and display mutations involving different genes includingKRAS, BRAF, ERBB2, PTEN, PIK3CA, CTNNB1andARID1A.Type 2 tumours are genetically highly unstable and harbourTP53, BRCA 1andBRCA 2mutations.High‐grade serous carcinoma and low‐grade serous carcinomas develop from fallopian tube epithelium and serve as the prototypes of type 2 and type 1 pathway respectively.Low‐grade endometrioid carcinomas and clear cell carcinomas commonly develop from endometriotic cysts.The presence ofTP53mutations correlates with high grade tumours and poor prognosis.The presence of mutations ofBRCA 1andBRCA 2genes indicate good treatment response to platinum compounds and PARP inhibitors.
Genetic Modifiers of Neurological Disease
Authors: Kearney Jennifer A , Jorge Benjamin S 
Published: April 2013

AbstractGenetic modifiers make a significant contribution to the pathophysiology of neurological disease. A common feature of heritable neurological disease is phenotype variation among patients with the same mutation. Some of the observed phenotype variation can be attributed to genetic modifiers. Identifying modifier genes in humans is challenging due to limitations of sample size and confounding environmental effects. Complementary approaches in model organisms can facilitate the identification and characterisation of modifier genes. Identifying genetic modifiers can help elucidate the genetic and molecular basis of neurological disease. This knowledge can be used to improve genetic risk assessment and foster the development of personalised therapeutic strategies based on molecular diagnosis.Key Concepts:Genetic modifiers contribute to phenotype variability in neurological disorders.Model organisms are a useful system for identifying modifier genes and studying underlying mechanisms.Synergy between human genetics and model systems can facilitate modifier gene identification and validation.Identifying pathways that are influenced by gene modifiers may suggest novel therapeutic strategies.
Genetics of Diseases of the Nuclear Envelope
Authors: Muchir Antoine 
Published: April 2013

AbstractMutations inlamin A/C gene(LMNA) gene, which encodes A‐type nuclear lamins, cause a diverse range of diseases called laminopathies. These diseases selectively affect different tissues and organ systems. The main function of A‐type nuclear lamins is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organisation, connecting the nucleus to the cytoplasm, gene transcription and mitosis. Since the first mutations inLMNAthat causes a human disease identified in 1999, the A‐type lamins get a lot of focus from the scientific community. More than a decade later, promising therapeutic approaches emerge that will hopefully lead to new ways to treat or prevent laminopathies.Key Concepts:LMNAgene encodes ubiquitously expressed nuclear A‐type lamins.LMNAmutations cause several diseases affecting specific tissues or progeroid syndrome, that is, laminopathies.Studies on mouse models ofLMNA‐dilated cardiomyopathy showed that MAP kinase and AKT/mTOR signalling are abnormally activated.Post‐translational modifications of lamin A are important for the pathogenesis of progeria.Small molecules have been successfully usedin vivoto alleviate the symptoms ofLMNA‐dilated cardiomyopathy and progeria.
Genetics of the Ribosomopathies
Authors: Liu Johnson M , Lipton Jeffrey M , Ellis Steven R 
Published: April 2013

Abstract

Ribosomopathies refer collectively to a group of disorders characterised by disruption of ribosome synthesis. Classically, these are rare genetic syndromes with developmental abnormalities, often involving abnormal blood cell production, as seen in Diamond Blackfan anaemia, the 5q‐myelodysplastic syndrome and Shwachman‐Diamond syndrome or causing craniofacial anomalies (Treacher Collins syndrome). However, research has recognised several new putative ribosomopathies (Bowen‐Conradi syndrome and North American Indian childhood cirrhosis), and new revelations may force the reclassification of some older disorders (dyskeratosis congenita and cartilage hair hypoplasia). Finally, some, but not all, ribosomopathies predispose patients to solid tumours or haematologic malignancies. Here, we critically review the underlying genetics in old and new ribosomopathies and examine the pathophysiologic consequences of aberrant ribosome biogenesis.

Key Concepts:

Ribosomopathies refer collectively to a group of disorders characterised by disruption of ribosome synthesis.

Most ribosomopathies are rare genetic syndromes with developmental abnormalities, often involving abnormal blood cell production or causing craniofacial anomalies.

There are several new putative ribosomopathies and the classification of some disorders is in flux.

Diamond‐Blackfan anemia and Treacher Collins syndrome are two well‐described ribosomopathies that share pathophysiologic similarities but have different clinical manifestations for the most part.

Some, but not all, ribosomopathies predispose patients to solid tumours or haematologic malignancies.
Epigenetic Drivers of Genetic Alterations in Cancer
Authors: Suzuki Hiromu 
Published: April 2013

AbstractIn cancer cells, aberrantdeoxyribonucleic acid(DNA) methylation plays key roles in the epigenetic dysregulation of tumour‐related genes, thereby affecting numerous cellular processes. Here we discuss the mechanism by which epigenetic events drive genetic alterations in cancer. Epigenetic inactivation of mutL homolog 1 (MLH1) is a major cause of microsatellite instability, while methylation ofO‐6‐methylguanine‐DNA methyltransferase (MGMT) is often associated with specific mutations. In addition, the silencing of breast cancer 1 (BRCA1), Fanconi anemia, complementation group F (FANCF) and checkpoint with forkhead and ring finger domains (CHFR) impairs the machinery involved in maintaining genomic integrity. Conversely, a recently discovered link betweenisocitrate dehydrogenase 1 (IDH1)/2or tet methylcytosine dioxygenase 2 (TET2) mutations and genome‐wide aberrant methylation suggests the hypermethylator phenotype may lie downstream of genetic alterations. Dissecting the association between epigenetic and genetic alterations could provide important clues for developing novel approaches to the treatment of cancer.Key Concepts:Epigenetic alteration of driver genes can lead to genetic alterations in cancer.Epigenetic drivers include genes involved in DNA repair and cell cycle checkpoints.Global hypomethylation may be another epigenetic driver that induces chromosomal instability.Epigenetic alteration of driver genes is often associated with the CpG island methylator phenotype (CIMP).The CIMP may lie downstream of specific gene mutations.
Genetics of Dementia
Authors: Russell Michael Bjørn 
Published: April 2013

Abstract

Dementia is a syndrome and not a single disease. It is caused by a primary brain disorders or a neurological/somatic disorders with brain involvement. Alzheimer disease is the most common dementia. Approximately 1% have early‐onset Alzheimer disease, often caused by mutation in the

APP

,

PSEN1

or

PSEN2

gene. Late‐onset Alzheimer disease has a complex inheritance. The

APOE

ɛ4 allele is a major risk factor for late‐onset Alzheimer disease, while the ɛ2 allele has a protective effect. Genome‐wide association studies indicate that

BIN1

,

CRI

,

CLU

and

PICALM

play a role in late‐onset Alzheimer disease, while other potential genes requires further investigation. Stroke is a syndrome and not a single disease. CADASIL is the most common autosomal dominant inherited cause of stroke and vascular dementia caused by mutations in the

NOTCH3

gene. It is the stroke itself rather than the underlying vascular risk factors that cause the dementia.

Key Concepts:

Dementia is a syndrome and not a single disease.

Alzheimer disease is the most common primary brain disorders causing dementia.

Early‐onset (≤60‐year‐old) familial Alzheimer disease is caused by mutation in the
APP
,
PSEN1
or
PSEN2
gene in 30–50% of the families.

Late‐onset (>60 years old) Alzheimer disease have multifactorial inheritance.

Linkage and association studies have been largely unsuccessful, for reasons that include small sample size, low sensitivity to detect moderate effects and the substantial locus heterogeneity that underlies late‐onset Alzheimer disease.

The
APOE
ɛ4 allele is a major risk factor for late‐onset Alzheimer disease, while the ε2 allele has a protective effect.

Genome‐wide association studies indicate that
BIN1
,
CRI
,
CLU
and
PICALM
play a role in late‐onset Alzheimer disease.

Vascular dementia is the most common secondary brain disorder causing dementia.

Stroke is a syndrome and not a single disease and it is the stroke itself rather than the underlying vascular risk factors that cause the dementia.

CADASIL is the most common autosomal dominant inherited cause of stroke and vascular dementia caused by mutations in
NOTCH3
.
Genetics of Susceptibility to Tuberculosis
Authors: Stein Catherine M 
Published: April 2013

Abstract

There is an increasing body of evidence showing that tuberculosis (TB) susceptibility is partially influenced by human genetic factors. Early evidence came from twin studies, observation of differences in susceptibility between ethnic groups, animal models and segregation analysis. Both candidate gene and genome‐wide studies have been conducted to search for genes underlying this susceptibility, and there has been very little consistency in the results across these studies. This inconsistency may be partially explained by the complexity of TB as a phenotype, differences across populations in both population genetic parameters as well as patterns of

Mycobacterium tuberculosis

strain variation, and interacting factors such as HIV, age, sex and other genes. Future studies are needed to further examine these factors as well as the immune response underlying TB pathogenesis.

Key Concepts:

Several types of studies provide evidence for a role of human genetics in susceptibility to tuberculosis (TB).

There have been numerous candidate gene studies conducted, and 10 genome‐wide studies conducted, but there is little overlap in the results of these studies.

Studies of TB genetics are extremely sensitive to phenotype definition in both cases and controls.

There are many aspects of the design of previous studies that make them difficult to compare.

Several aspects of TB require further study, including the role of variable strain virulence, immune response to TB, and the role of rare variants and copy number variants.
Erdmann, Rhoda
Authors: Brigitte Hoppe 
Published: April 2013

Abstract

Rhoda Erdmann was one of the pioneer women in university Science in Europe. Based on regular university studies she earned a doctoral degree in biology at Munich in 1908. Continuing research on protozoa at Berlin, she was invited by the Yale University, USA, in 1913 and became a faculty member (1915–1918). During World War I she lost this position, but could not return to Germany before 1919. In spite of obstacles she established the first department for experimental cell research at Berlin University in 1919 and published the first German textbook for ‘explantation’ and tissue culture in 1922. Two habilitations (in biology 1920, in medicine 1923) enabled her together with her scientific school to develop studies of tissue culture fundamental for biological and medical research. Owing to her international reputation she found the journal for experimental cell research in 1925 and international congress for cytologists in 1930. Her activities were ended by the National Socialists’ coming into power in 1933, when the laboratory work was interdicted to her.

Key Concepts:

After having stated the principal morphological parts of animal and human cells until around 1900, it became an aim of biology to search for their physiological qualities and significance for the life processes.

Biologists expected new insights into elementary life processes by studying reproduction states and conditions of protozoa, that is, single‐celled organisms, at the beginning of the twentieth century.

Special methods of tissue culture and single cell cultivation became fundamental for research in many biological and medical fields from the beginning of the twentieth century onwards.

The following new institutions and publications are fundamental for the development of a new research area: establishing a special institute for research and teaching, founding an organ to publish research results and conferences for international exchange, intensifying teaching by a textbook for students and young scholars.

International contacts further not only the individual scientific work and career of a scientist, but support also the development of a new branch of science.

Different political and social systems of the countries of former Germany impeded the integration of women within the higher education and university system until the first decades of the twentieth century.

The life and career of R. Erdmann shows clearly, how much the development of the scientific work and the personal career of a woman was hindered in former Germany by a defective and inadequate support from the side of people responsible for the education of the youth and also for the advancement of science.
Sager, Ruth
Authors: Sapp Jan 
Published: April 2013

Abstract
Ruth Sager pioneered two fields of genetics, challenging orthodoxy and in so doing opening up new fields for investigation. Beginning in the 1950s, at a time in which geneticists generally maintained that all genes were located in the chromosome of the cell nucleus, Ruth Sager showed that chloroplasts possessed their own genome, and worked out the standard methods for studying chloroplast genes, and their interactions with nuclear genes. Then in the 1970s Sager turned her skills to studying cancer genetics; when attention was focused on the recent discovery of cancer‐causing ‘oncogenes’, Sager took a wholly different approach: she hypothesised the existence of tumour‐suppressor genes, provided evidence for their existence, and demonstrated that such genes were inactivated in tumours.
Stevens, Nettie Maria
Authors: Ogilvie Marilyn Bailey 
Published: April 2013

Abstract

Nettie Stevens has been recognised recently for her careful research postulating that the chromosomes are involved in the inheritance of a specific character, sex. The background of her achievement is discussed, including the behaviour of the chromosomes in cell division, the results of experimental breeding, and the possibility that the two are related. Through exploring her early life and education, her relationship to her colleagues who, while praising her work, did not give her the credit she deserved, and the professional difficulties that she as a woman encountered, Stevens’ importance in the history of genetics is considered.

Key Concepts:

Nettie M. Stevens is most noted for postulating that sex is determined by a specific chromosome.

Stevens shares credit for this discovery with Edmund B. Wilson.

Wilson is more often credited for this discovery both because he made more contributions to the history of biology and because Stevens was a woman.

The discovery of the sex chromosome helped establish the idea that chromosomes were responsible for the inheritance of a specific characteristic, sex.
Evolution and Function of the RelA/SpoT Homologue (RSH) Proteins
Authors: Atkinson Gemma C , Hauryliuk Vasili 
Published: April 2013

AbstractRelA/SpoT Homologue (RSH) proteins comprise a superfamily of enzymes that synthesise and/or hydrolyse the nucleotide alarmone ppGpp, mediator of the ‘stringent’ response and regulator of cellular metabolism in response to changing environmental conditions. Most of what we know about RSHs comes from theEscherichia coliproteins RelA and SpoT, paralogues that appear to have evolved from duplication of an ancestral Rel gene in the lineage to β‐ and γ‐proteobacteria. Recently, more details have come to light on the evolution of the RSH superfamily, revealing that there is a much greater diversity of RSHs than previously thought.Key Concepts:Various stress conditions (amino acid, iron and fatty acid starvation, heat shock, etc.) induce the so‐called ‘stringent response’ in bacteria and chloroplasts.The stringent response is mediated by RelA/SpoT Homologue (RSH) proteins that modulate intracellular concentration of the ppGpp alarmone nucleotide.ppGpp exerts its regulatory role by binding and modulating activity of several targets: the RNA polymerase, translational GTPases EF‐G and IF2, lysine decarboxylase Ldc1, polynucleotide phosphorylase, DnaG primase and others.RelA senses amino acid starvation by directly interacting with the 70S ribosome and inspecting the aminoacylation status of the A‐site tRNA, and responds to the presence of deacylated tRNA by synthesising ppGpp.SpoT is a bifunctional enzyme that has both ppGpp synthetic and hydrolytic activities and senses several cues that modulate its net activity.Phylogenetic analyses divide the RSH protein family into 30 subgroups comprising three groups: long RSHs (such as RelA and SpoT), small alarmone synthetases (SASs) and small alarmone hydrolases (SAHs).In addition to bacteria and chloroplasts, RSH proteins have been identified in eukaryotes and isolated species of archaea, however the ppGpp‐mediated stringent response has not yet been identified in these organisms.In eukaryotes, amino acid starvation is sensed by the general amino acid control (GAAC) system that is nonhomologous to the RSH system but is functionally analogous.