bluuebunny/crossref_metadata_2025 huggingface dataset:
Microsatellites
Authors: Epplen Jörg T , Akkad Amer D
Published: April 2013

Microsatellites are short, in‐tandem arranged repetitive
deoxyribonucleic acid
(DNA) elements which are widespread in eukaryotic and prokaryotic genomes. The basic unit lengths of microsatellites (or simple DNA sequence repeats) comprise up to six (or eight) nucleotides, and these motifs are perfectly reiterated from 5 to more than 100 times. Longer and more imperfectly reiterated periodicities border on the definitions of the so‐called minisatellites. Microsatellites have been utilised as markers for population genetic studies, forensic and relatedness testing, investigations on genetic diversity and the identification of genetic traits. Albeit constituting elusive model disorders, microsatellite expansion diseases are rather rare entities characterised by differential pathogenetic pathways. Hence microsatellites exhibit a broad spectrum of biological relevance ranging from selfish or neutral to pathogenic elements.

Key Concepts:

Microsatellites exhibit perfect tandem repetition of short nucleotide motifs.

Microsatellites represent most variable components throughout most genomes.

The biological significance of microsatellites ranges from selfishness and molecular marker for a small genome region to disease causing mutation when expanded, respectively.
Tuberous Sclerosis: Genetics
Authors: Tee Andrew R , Sampson Julian R , Davies D Mark
Published: April 2013

Tuberous sclerosis is an autosomal‐dominant disorder characterised by seizures, intellectual disability, autistic spectrum disorder and the growth of benign tumours in multiple organs including the brain, skin, heart and kidneys. It is caused by mutations in either the
TSC1
gene on 9q34 or the
TSC2
gene on 16p13.3. The gene products, TSC1 and TSC2, interact and as a heterodimer act to integrate multiple of stimuli such as mitogenic stimulation, oxygen and energy levels into the control of diverse cell processes. One of the best characterised downstream targets of TSC1/TSC2 is mammalian target of rapamycin complex 1 (mTORC1), which regulates proteins synthesis, metabolism, autophagy and cell division amongst other cellular processes. Clinical trials in patients with tuberous sclerosis using mTOR inhibitors have shown promising results.

Key Concepts:

Tuberous sclerosis is an autosomal‐dominant multisystem disorder.

Tuberous sclerosis is caused by mutations in either of two genes
TSC1
or
TSC2
.

One of the key functions of the TSC1/TSC2 protein complex is to integrate signals from multiple stimuli to regulate cellular processes such as growth and division via the mammalian target of rapamycin (mTOR) pathway.

Knowledge of the molecular pathology of tuberous sclerosis has been translated into clinical trials using mTOR inhibitors to treat manifestations of the condition.
Monogenic Hypercholesterolemia: Genetics
Authors: Day Ian N M
Published: April 2013

Several specific genes, when mutated, cause high blood cholesterol levels, with consequent early atherosclerosis and coronary events. The classical example and commonest defects involves the low‐density lipoprotein receptor (LDLR) gene, haploinsufficiency of which leads to slow LDL‐cholesterol clearance and homozygous mutation of which leads to extreme hypercholesterolaemia and coronary disease during childhood. Familial defective apolipoprotein B (FDB) involvingAPOBtransmits as an autosomal dominant trait with incomplete penetrance and affects ApoB, the ligand within LDL particles for the receptor.PCSK9also transmits as an autosomal dominant trait, with high penetrance. PCSK9, proprotein convertase subtilisin kexin type‐9, is secreted and by binding to the LDL receptor promotes receptor degradation, gain‐of‐function mutations increasing binding and reducing receptor availability. LDLRAP1, a clathrin adaptor protein, if defective on both alleles, causes autosomal recessive hypercholesterolaemia in which there is failure to internalise the receptor. Knowledge of these new genes has identified new targets for pharmaceutical developments and mutation analysis has contributed diagnostically to cascade screening now in use to identify and offer preventive treatment.

Key Concepts:

Single gene mutations can cause inherited familial patterns of hypercholesterolaemia.

The monogenic hypercholesterolaemias all involve genes encoding products participating in the pathway of LDL particle clearance by the LDL receptor.

LDLR defects represent a genocopy for the phenotype of dietary hypercholesterolaemia and offer inference about the causal role of population hypercholesterolaemia in coronary risk.

Four genes are known which can cause an inherited hypercholesterolaemia, these areLDLR,APOB,PCSK9andLDLRAP1.

The patterns of inheritance differ,LDLR,APOBandPCSK9causing autosomal dominant hypercholesterolaemia,LDLRAP1causing autosomal recessive hypercholesterolaemia.

Mutations inPCSK9mutations involve gain‐of‐function, whereasLDLR,APOBandLDLRAP1mutations involve loss of function.

PCSK9 in particular represents a potential novel target for new pharmaceutical development of cholesterol lowering drugs.

Mutation knowledge and mutation identification now support cascade screening to identify and offer treatment to individuals at high risk of early coronary disease.
Disclosing Genetic Information to Family Members: The Role of Empirical Ethics
Authors: Dupras Charles , Ravitsky Vardit
Published: April 2013

The familial and predictive nature of genetic information raises ethical issues regarding its disclosure to biological relatives. Arguments in the bioethics literature have centered on the right of the patient to privacy and confidentiality versus the right of family members to receive information that is clinically relevant to them. Empirical research has shown that although the need for disclosure within the family is rarely contested by patients, they are preoccupied by the ethical dimensions of their ‘genetic responsibility’, share a desire to protect relatives from the possible adverse effects of disclosure, and need guidance regarding what, why, to whom, when and how genetic information should be disclosed to mitigate adverse outcomes. Empirical ethics thus contributes to important insights and help reframe the debate to better address the lived experiences of patients, family members and healthcare professionals.

Key Concepts:

Disclosure of genetic information within the family raises particular ethical issues.

The disclosure debate has been framed as a conflict between respect for autonomy (i.e. the duty of the clinician to respect patient confidentiality) and beneficence/‘do no harm’ (i.e. the clinician's duty to warn others).

It is suggested that a patient's relatives have a right to know genetic information when it is clinically relevant to them.

Most patients feel a genetic responsibility to inform family members in order to promote their health and well being.

Empirical studies have shown that disclosure decisions are complex and influenced by numerous factors.

Empirical ethics involves empirical studies which provide information that can frame ethical debates, enhance normative analysis and inform clinical practices.
Limb Development Anomalies: Genetics
Authors: Manouvrier‐Hanu Sylvie , Florence Petit , Holder‐Espinasse Muriel , Escande‐Narducci Fabienne
Published: April 2013

Congenital limb malformations range from reduction defects to subtle digit anomalies (number/length/anatomy). Their prevalence is evaluated from 1.3‰ to 1.9‰ neonates. They can be classified as disruption anomalies and genetic malformations. The later are due to limb development gene function alteration and may be isolated or associated with other malformations.

The genes implicated in the limb bud development are numerous. They work together to trigger limb bud growth (proximodistal axis), polarisation (antero‐posterior and dorsoventral) and patterning. They are often pleiotropic, explaining the frequent association of limb anomalies with other malformations.

Furthermore, limb malformations are often genetically heterogeneous and various anomalies of one single gene can cause different diseases (allelic heterogeneity).

Key Concepts:

The limb bud development requires a constant equilibrium between cell mitotic activity and apoptosis.

The limb bud growth, its antero‐posterior and dorsoventral polarisation as well as its patterning are very interlinked and imply precise space and time regulation of the implicated genes’ expression.

Regulators/enhancers
: Alterations of regulatory elements of key developmental genes play an important role in limb bud development. (For example the Zone of polarising activity Regulatory Sequence (ZRS) is a crucial regulator of SHH expression in the limb bud.)
Colour Vision Defects
Authors: Neitz Maureen , Mancuso Katherine , Neitz Jay
Published: April 2013

Normal colour vision refers to the form of trichromatic colour vision shared by most individuals. It is mediated by three types of retinal cone photoreceptors, short‐ (S), medium‐ (M) and long‐ (L) wavelength‐sensitive. Colour vision defects can either be inherited as the consequence of genetic defects that affect the function of one or more cone type, or they can be acquired through exposure to neurotoxins or as secondary effects of systemic or ocular diseases. Among individuals with colour vision deficiency, there is tremendous variation in the capacity for colour vision, ranging from no colour vision to nearly normal. Viral‐mediated gene therapy for ocular diseases has been an area of intense investigation over the last decade. Because genetic mutations underlying colour vision deficiencies have been identified, gene therapy may be a viable option for curing various forms of colour blindness in the future.

Key Concepts:

Normal colour vision requires three classes of cone photoreceptor in the retina: short‐, medium‐ and long‐wavelength sensitive.

The hallmark feature of colour vision defects is a reduction in the number of different colours that can be distinguished from each other.

Colour vision defects can either be inherited or they can be acquired secondary to disease or through exposure to certain drugs or neurotoxins.

Mutations and rearrangements in the genes encoding the short‐, medium‐ and long‐wavelength sensitive photopigments are responsible for inherited colour vision deficiencies.

Gene therapy has been successfully used to treat colour blindness in animal models and these experiments pave the way towards cures for colour blindness in humans.
Drug‐Metabolising Enzymes: Genetic Polymorphisms
Authors: Ingelman‐Sundberg Magnus
Published: April 2013

Polymorphism in drug‐metabolising enzymes is of great importance for interindividual differences in drug therapy. Variant genes causing increased, decreased or abolished drug metabolism influences the drug response and risk for adverse drug reactions. The genetic alterations include single‐nucleotide polymorphisms, ins/del and gene copy number variations. Of particular importance are the cytochrome P450 enzymes responsible for the metabolism of the majority of clinically important drugs. This variability is now emphasised during drug development and of importance for routine drug prescription. Several different drugs contain pharmacogenomic labels where genotyping before prescription is mandatory or recommended. Predictive genotyping of drug‐metabolising genes can thus help to design individualised, safer and more efficient drug therapies.

Key Concepts:

The majority of drug metabolism is carried out by cytochrome P450 enzymes.

The polymorphic cytochrome P450 enzymes account for 40% of the phase I drug metabolism.

The major phenotypes with respect to drug metabolism are poor metabolisers (PMs), intermediate metabolisers (IMs), extensive metabolisers (EMs) and ultrarapid metabolisers (UMs).

There are large interethnic differences in the drug metabolism caused by genetic factors.

The toxicity of some anticancer drugs, and antibiotics can be predicted by the occurrence of particular genes encoding drug‐metabolising enzymes.

The effective dose of clopidogrel, warfarin, tricyclic antidepressants, tamoxifen and some antipsychotics is determined by the P450 polymorphism.

Irenotecan and mercaptopurine toxicity is dependent on UGT1A1 and TPMT polymorphism, respectively.

85% of the pharmacogenomic drug labels refer to genes encoding drug‐metabolising enzymes, in particular cytochrome P450.
Charcot–Marie–Tooth Disease and Associated Peripheral Neuropathies
Authors: Espinós Carmen
Published: April 2013

Charcot–Marie–Tooth (CMT) disease, a hereditary motor and sensory neuropathy, is the most frequent inherited neuromuscular disorder. According to electrophysiological and nerve biopsy criteria, CMT is classified into three categories: demyelinating, axonal and intermediate. Mutations in more than 30 genes/loci result in CMT phenotype. The main demyelinating CMT form is a 1.4‐Mb duplication, which affects the
PMP22
(70%) gene, followed by mutations in the
GJB1
(6%) and
MPZ
(3–5%) genes. Regarding axonal CMT, the commonest form is due to mutations in the
MFN2
(20%) gene. Other neuropathies that share clinical similarities and genetic basis with CMT include Déjérine–Sottas syndrome, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsies. During the last decade advances have allowed to get insight of the molecular bases of this group of peripheral neuropathies and in most cases, an accurate genetic diagnosis is possible.

Key Concepts:

The Charcot–Marie–Tooth (CMT) disease, a hereditary motor sensory neuropathy, is the most frequent inherited neurological disease.

According to electrophysiological and histopathological criteria, CMT can be classified into three forms: demyelinating, axonal and intermediate.

Genes involved in Déjérine–Sottas syndrome, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsies are also associated with CMT.

CMT is characterised by a wide genetic heterogeneity because more than 30 genes/loci are related to this disease and also because all the Mendelian patterns can be found in this group of diseases.

The duplication of 1.4 Mb which affects the
PMP22
gene (CMT1A duplication) is the most prevalent cause of Charcot–Marie–Tooth disease with a percentage of 43% of the total CMT.

Once the most frequent genes related to CMT (
PMP22
,
MPZ
,
GJB1
,
MFN2
and
GDAP1
) have been ruled out, mutations in the remaining known genes occur in less than 1% of CMT cases.

The complexity of CMT genetics makes difficult to identify the disease‐causing mutation in many cases and therefore, the next‐generation sequencing (NGS) technologies facilitate the genetic diagnosis.
Chemical, Biological, Radiological and Nuclear Weapons: Genotoxicity
Authors: Gosden Christine M , Gardener Derek
Published: April 2013

Many chemical, biological radiological and nuclear weapons (CBRN) including mustard gas, nerve agents, Aflatoxin, nuclear and radiological weapons are genotoxic, neurotoxic and carcinogenic. They damage
deoxyribonucleic acid (DNA)
, cells, tissues and organs. Almost every decade since World War I (WWI) has seen CBRN manufacture or use, killing and injuring many hundreds of thousands. Survivors of CBRN use (WWI victims, WWII manufacture in Germany, Japan, UK, US and of Conflicts involving CBRN use, such as Northern Iraq, Afghanistan) face increased risk of cancers, infertility, medical disorders and reproductive health effects. Each agent has specific effects, for example, Aflatoxin causes liver cancer and is embryotoxic, Mustard gas, Nuclear and Radiological weapons cause haematological malignancies and solid tumours. This indicates each type of weapon causes specific types of genomic damage. Knowledge of the mechanisms of action of CBRN is important in identifying CBRN use, developing therapies to aid victims and counteracting the threats from these weapons.

Key Concepts:

Despite the Geneva Convention of 1925 prohibiting their use, CBRN have been widely used over the past 100 years in wars and conflicts to subjugate populations, kill and injure.

CBRN are genotoxic and neurotoxic leading to long‐term genomic damage and major risks for survivors of exposures.

There are currently few methods of identifying genomic damage in victims of CBRN; new methods such as next generation genome and transcriptome sequencing will allow the identification of damage and predict methods for screening, protection and treatment.

CBRN may be used by rogue governments or terrorist groups to kill, maim and cause long‐term medical damage.

CBRN have been used in ethnic cleansing campaigns, against guerrilla forces in mountainous regions as well as conventional wars and conflicts resulting in lethality and premature deaths through cancers, medical disorders, embryonic, fetal and infant deaths, birth defects and infertility, leading to ‘silent attrition’ of targeted populations.

There are no known treatments for CBRN damage as these agents cause long‐term irreversible genotoxic and neurotoxic damage; key elements for protection are to identify CBRN use, develop screening methods to identify those exposed, reduce ongoing contamination of food, water and environment, treat victims and develop therapies risks.
Genetics of the Autosomal Dominant Spinocerebellar Ataxias
Authors: Corral‐Juan Marc , Corral Jordi , San Nicolás Héctor , Volpini Victor , Matilla‐Dueñas Antoni
Published: April 2013

The spinocerebellar ataxias (SCAs) are a clinically, genetically and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and noncerebellar symptoms that, in many cases, defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its rely connections. Currently, there are 43 different genes associated with the autosomal dominant SCAs identified. Genetic studies refine the clinical diagnosis, provide molecular testing of at risk, a/presymptomatic, prenatal or preimplantation and facilitate genetic counselling in 27 SCA subtypes. Recent scientific advances are shedding light into the altered molecular pathways involved and the mechanisms by which the mutant gene products underlie neurodegeneration. This knowledge should be translated into effectively developing selective therapeutic strategies. The scope of this chapter is to provide an updated summary of the genetic aspects of the autosomal dominant SCAs.

Key Concepts:

Ataxia, a term that derives from the Greek, is a neurological disorder characterised by loss of control of voluntary body movements.

Spinocerebellar ataxias, also known as SCAs, are a highly heterogeneous group of neurodegenerative diseases caused by cerebellar atrophy triggered by predominant loss of Purkinje cells in the cerebellum.

The term ‘spinocerebellar ataxias’ is commonly used for those inherited progressive, congenital or episodic ataxias presenting an autosomal dominant inheritance.

Mutations presenting incomplete penetrance in at least 43 genes are responsible for ataxia in the autosomal dominant SCAs.

CAG repeat expansions encoding for polyglutamines in the gene products currently underlie neurodegeneration in seven spinocerebellar ataxia subtypes.

Anticipation is a genetic phenomenon whereby the clinical symptoms become apparent at an earlier age as it is passed on to the next generation. This is associated with the germline transmission of an unstable expanded CAG‐triplet repeat.
Albinism: Genetics
Authors: Oetting William S
Published: April 2013

Albinism has classically been described as the complete absence of melanin pigment in the skin, hair and eyes throughout the life of the affected individual. Modern molecular analysis has shown that albinism is a much more complex genetic disorder than previously thought, involving many genes with an array of functions, as well as great variation in the phenotype of affected individuals. There are currently 15 genes that have been associated with albinism, including four nonsyndromic forms of oculocutaneous albinism (reduced pigment affects skin, hair and eyes), one nonsyndromic form of ocular albinism (reduced pigment affects eyes only) and ten syndromic disorders that include albinism as part of the phenotype. The gene functions of the nonsyndromic forms are thought to be involved in melanin biosynthesis and many of the genes associated with the syndromic forms are involved in protein trafficking. Common genetic variants within some of these genes are also associated with normal variation in eye, hair and skin colouration.

Key Concepts:

All animals make melanin as the chief form of colouration.

Melanin is made in specific cells called melanocytes.

Albinism is caused by an absence of melanin biosynthesis resulting in several clinical features.

There are many different types of albinism.

There are several genes associated with albinism.

The molecular pathology of albinism is complex and involves different types of mutations.

Variation in skin pigmentation involves common polymorphisms in some albinism‐related genes.

Albinism can affect interactions between individuals and society.
Human Disease and the Desmosome
Authors: Chidgey Martyn
Published: April 2013

Desmosomes are intercellular junctions of epithelia and cardiac muscle. They are located at the cell membrane where they act as anchors for intermediate filaments. Desmosomes maintain the structural integrity of tissues and disruption of desmosomal adhesion can have devastating consequences for human health. Arrhythmogenic right ventricular dysplasia, a heart muscle disease that is characterised by life‐threatening arrhythmias and increased risk of sudden heart failure, is caused by mutations in genes encoding desmosomal proteins. Other mutations can result in severe skin blistering, catastrophic fluid loss and early death. Cardiocutaneous syndromes that affect the heart, skin and hair are also caused by mutations in desmosomal genes. Pathogenic autoantibodies against desmogleins, membrane‐spanning proteins of desmosomes, cause the skin blistering diseases pemphigus and staphylococcal scalded skin syndrome. Desmosomes and their constituents could contribute to the progression of cancer.

Key Concepts:

Desmosomes are intercellular junctions of epithelia and cardiac muscle.

Desmosomes maintain the structural integrity of tissues.

Mutations in genes encoding desmosomal proteins can result in heart disease and disorders of the skin and hair.

Pemphigus is an autoimmune skin blistering disease that is caused by autoantibodies against desmogleins, membrane‐spanning proteins of desmosomes.

Desmosomes may be important in cancer.
Lesch–Nyhan Disease
Authors: Visser JE , Jinnah HA
Published: April 2013

Lesch–Nyhan disease (LND) is an X‐linked, inherited neurodevelopmental disease caused by a mutation in the gene encoding the purine salvage enzyme
hypoxanthine guanine phosphoribosyltransferase
(HPRT). Virtual absence of
HPRT
is associated with hyperuricemia and specific neurobehavioural features: a hyperkinetic movement disorder dominated by dystonia, cognitive impairment with attentional and executive deficits, and behavioural disturbances including self‐injurious behaviour. Partial
HPRT
deficiencies result in incomplete phenotypes characterised by hyperuricemia with or without neurological dysfunction, but without self‐injury.
HPRT
deficiency leads to a deficiency of the neurotransmitter dopamine, and the subsequent dysfunction of the basal ganglia is thought to play an important role in the pathogenesis of the neurobehavioural phenotype. Administering allopurinol reduces the risk of hyperuricemia‐associated urological and articular complications, but there is currently no effective treatment for the neurobehavioural features of LND. Self‐injurious behaviour is managed by restraints and soft padding of the environment, and sometimes neuroleptics, anxiolytics or sedatives.

Key Concepts:

Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme
hypoxanthine guanine phosphoribosyltransferase
(HPRT).

LND is characterised by developmental delay, hyperuricemia, dystonia, attentional and executive deficits and behavioural disturbances including self‐injurious behaviour.

The severity of the clinical phenotype in LND depends on the amount of residual
HPRT
enzyme activity.

Dysfunction of the basal ganglia dopamine systems are thought to play an important role in the pathogenesis of the neurobehavioural phenotype.

LND patients are not globally retarded, but rather have impairments in specific cognitive domains, including attentiveness and mental flexibility.

Compulsive self‐injurious behaviour is considered a hallmark of the disease, and emerges usually within the first few years of life.

HPRT
enzyme activity testing or
HPRT
gene mutation analysis confirms the diagnosis.

As effective treatment for LND is currently lacking, prevention through carrier testing, genetic counselling and prenatal diagnosis is of utmost importance.
Peroxisome Biogenesis Disorders
Authors: Fujiki Yukio
Published: April 2013

Peroxisome biogenesis disorders (PBDs) are autosomal recessive, progressive disorders characterised by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of 13 complementation groups (CGs). Two mutually distinct but complementary approaches, forward genetic approach using more than a dozen CGs of peroxisome‐deficient Chinese hamster ovary (CHO) cell mutants and the homology search by screening the human expressed sequence tag (EST) database using yeast peroxin (

PEX

) genes, have been taken in order to isolate mammalian

PEX

genes. Search for pathogenic genes responsible for PBDs of all 13 CGs is now accomplished. Prenatal DNA diagnosis using

PEX

genes is now possible for PBDs of all 13 CGs. Moreover, molecular mechanisms underlying peroxisome biogenesis involving membrane assembly and matrix protein import are currently investigated by making use of

PEX

genes and

pex

cell mutants.

Key Concepts:

A single cell comprises more than a dozen different organelles that have unique protein compositions. Mechanisms underlying when and how these proteins are transported should be defined.

The ways how the diverse sequences of proteins are recognised for translocation by the transport systems/machineries need to be delineated.

The proteins and the lipid environment catalysing the protein transport must be addressed.

Furthermore, during the cell cycle, each organelle must double in size, divide, and be delivered to its proper location in the daughter cells. How such events are accomplished and regulated should be defined.

In tackling such issues, genetic phenotype complementation screening using mammalian somatic cell mutants and by taking advantage of highly sensitive and rapid detection may lead to cloning of genes essential for protein trafficking and organelle assembly.

Mutations in genes are permanent alterations that may lead to changes in phenotype. Cell mutants are a highly useful tool in genetic, biochemical, as well as cell biological research.

Several methods including the most recent lipofection have been developed for transfecting DNA into animal cells.

Peroxisome biogenesis disorders (PBDs) are autosomal recessive, progressive disorders characterised by loss of multiple peroxisomal metabolic functions and defects in peroxisome assembly, consisting of more than a dozen complementation groups.

Genetic phenotype‐complementation of peroxisome assembly‐defective mutants of mammalian somatic cells such as Chinese hamster ovary (CHO) cells and of several yeast species including

Saccharomyces cerevisiae

and

Pichia pastoris

would lead to identification and characterisation of numerous genes that are essential for peroxisome biogenesis.
Hepatocellular Carcinoma
Authors: Zhao Xuelian , Elmore Lynne W , Harris Curtis C , Wang Xin Wei
Published: April 2013

Primary liver cancer is the third leading cause of cancer‐related deaths and fifth most common cancer in the world. Globally, estimated 877 000 people develop liver cancer and an almost equal number die of it in 2007. The worldwide prevalence, unique geographic distribution and well‐established aetiologic factors of hepatocellular carcinoma (HCC) have provided a strong impetus for elucidating mechanisms underlying the development of this aggressive malignancy. A better understanding of the specific molecular features of hepatocarcinogenesis has revealed clues for novel preventative and therapeutic strategies. Of particular note, the recent extraordinary progress in the genetic and genomic understanding of this disease may shed light on the molecular mechanisms of HCC progression and this knowledge may offer great opportunities for improving the treatment and prevention of HCC.

Key Concepts:

HBV, HCV, alcohol, aflatoxin, diabetes and obesity constitute the main risk factors for HCC.

Prediction of prognosis and response to therapy, screening of high‐risk cases and science‐based therapy are the challenging tasks to improve clinical medicine.

HCC is a highly heterogeneous disease, which exists between primary tumours from different individuals as well as within a single carcinoma, where subpopulation can range from primitive, stem‐like cells to foci of well‐differentiated malignant epithelium.

Both genetic and epigenetic changes contribute to HCC, the understanding of mechanisms behind those changes may lead to personalised HCC medicine.
Genetic Counselling: Consanguinity and Cultural Expectations
Authors: Karbani Gulshan A
Published: April 2013

Individual and familial responses to diagnosis of serious genetic disorders are known to vary widely. But within some minority ethnic groups, expectations and norms may act as a further influence upon these responses and thus render genetic counselling more problematic than usual.

This paper explores the implications of these cultural influences for ‘transcultural’ genetic counselling by focusing upon familial responses to diagnosis of a neuro‐degenerative disorder, Juvenile Sandhoff disease. Five out of seven cases in the UK health districts were linked to an extended family. These factors, along with ambivalent feelings around tests for ‘carrier’ status, can in part be explained by culturally mediated factors that included fears about the future marital and social prospects of children and the reactions from within the local communities. Genetic counselling in such cases thus not only needs to focus on the individual and family, but also reflect an awareness of these complex interactions between culture and attitudes. Recent development in the identification of gene, substrate deprivation and other potential treatments are beginning to be evaluated.

Key Concepts:

Genetic counselling: consanguinity and cultural expectations.

Autosomal recessive mode of inheritance.

Sandhoff disease is a life limiting neuro‐degenerative disorder characterised by an accumulation of GM2 gangliosidosises particularly in neurons. GM2‐Gangliosidosis, type 11 Hexosaminidases A and B deficiency. Children with Juvenile Sandhoff disease have ataxia, motor delay, walking deterioration, spasticity, and autism and learning difficulties.

With random mating, it has been estimated that frequency of affected is 1 in 360000. However, literature (Drousiotouet al, Hum Genet. 2000 Jul; 107(1):12‐7) suggests potentially large variations in carrier frequency in different ethnic populations; prevalence of disease likely to be especially high in autozygous populations.

Regional DNA laboratory has identified A missense mutation in ex11 (c.1376c>A (p.Asp459Ala) in the affected probands.

Genetic testing could replace biochemical testing to ascertain the carrier status in families where Sandhoff disease has been diagnosed. This offers the opportunity for pre‐marital testing for carriers in addition to the service of pre‐natal diagnosis since this may be culturally acceptable and requested by these families.

Despite some previous assumptions, contemporary UK minority families may be keen to take on screening and pre‐natal diagnosis.

Many of these families are keen to take advantage of new treatments in future as they become available.

These universal responses may be overlain by culturally mediated concern.

Culturally skilled counsellors are needed to work successfully within our diverse population.
Protein Glycosylation, an Overview
Authors: Lisowska Elwira , Jaskiewicz Ewa
Published: April 2013

Glycosylation is the most common post‐translational modification of proteins. It is a complex process involving many functional proteins and resulting in a great diversity of carbohydrate–protein bonds and glycan structures. Biological role of glycosylation and molecular and genetic basis of glycosylation disorders have recently been extensively explored. Glycosylation of some proteins has a great impact on their structures and functions, and interactions of protein‐linked glycans with carbohydrate‐specific proteins (lectins) modulate many important biological processes. Alterations in glycosylation occur in many pathological states, and genetically determined defects in glycosylation are the reason of severe diseases. The goal of this short article is to signalise the variety of problems of this vast field of research.

Key Concepts:

Glycosylation is one of the most important posttranslational modification of proteins.

There are various types of carbohydrate–protein glycosidic linkage and a great variety of structures of protein‐linked oligosaccharides (glycans).

The glycosylation process involves multiple proteins which are direct products of genes.

Protein‐linked glycans, as indirect gene products, show microheterogeneity, in qualitative and quantitative sense.

Glycosylation of proteins has a great biological significance, carbohydrate–protein interactions are involved in many biological precesses.

Alterations of glycosylation in many diseases are used for diagnostic and prognostic purposes.

Genetically‐based defects in protein glycosylation are the reason of severe diseases that is a direct evidence for the importance of glycosylation.

Various glycosylation pathways are studied as potential targets for therapeutic purposes.
Pattern Searches in Protein Sequences
Authors: Koua Dominique , Lisacek Frédérique
Published: April 2013

Common amino acid patterns characterise protein families. The results of automated searches for such patterns are used to qualify protein structure and function and to explore evolutionary relationships. Considering the increasing number of
deoxyribonucleic acid (DNA)
and protein sequences generated by high‐throughput technologies, pattern search is commonly undertaken in the identification of new protein function or the elucidation of biological processes. A wide array of pattern matching methods has been implemented. They aim at identifying the constraints governing the occurrence of amino acids in protein regions. These constraints are expressed as probabilities or as templates or both to set the basis of automated search.

Key Concepts:

Protein families are structured on the basis of common sequence patterns.

Patterns constrain the nature and the position of amino acids.

Patterns are matched to templates called signatures or profiles.

Computing significant scores in addition to building realistic predictive models are the basic requirements for accurate identification by pattern matching.
Noonan Syndrome
Authors: Tartaglia Marco , Gelb Bruce D
Published: April 2013

Noonan syndrome is a genetic disorder inherited as an autosomal trait or occurring sporadically, characterised by short stature, dysmorphic facies, webbed neck, congenital heart disease or hypertrophic cardiomyopathy, skeletal anomalies, cryptorchidism and developmental delay. Missense mutations in the
PTPN11
gene, encoding the protein tyrosine phosphatase SHP2, cause approximately 50% of cases. SHP2 is a positive regulator of RAS/mitogen‐activated protein kinase (MAPK) signal transduction. Noonan syndrome‐associated
PTPN11
mutations typically have gain‐of‐function effects on SHP2 and RAS/MAPK signalling. Missense mutations in other genes encoding proteins in the RAS/MAPK pathway, including
SOS1
,
KRAS
,
NRAS
,
RAF1
,
BRAF
and possibly
MEK1
, also cause Noonan syndrome. In aggregate, mutations in these seven genes account for approximately 70–75% of Noonan syndrome. Genotype–phenotype associations have been established with respect to particular genes and even mutations underlying this disorder.

Key Concepts:

Noonan syndrome is an autosomal dominant, pleomorphic trait characterised by short stature, typical facial dysmorphia and cardiovascular defects.

Noonan syndrome is a genetically heterogeneous trait, caused by missense mutations in genes encoding proteins in the RAS/mitogen‐activated protein kinase pathway.

Most mutations causing Noonan syndrome have gain‐of‐function effects resulting in increased RAS signalling.

Strong genotype–phenotype associations exist for genes and even specific alleles for Noonan syndrome.

The seven Noonan syndrome genes identified to date account for approximately 70–75% of cases.
Taste: Central Processing
Authors: Scott Thomas R
Published: April 2013

The taste system monitors the chemical environment to detect carbohydrates, proteins, fats and salt to be consumed and toxins to be avoided. It activates reflexes for swallowing or rejection, and powerful hedonic mechanisms of pleasure or disgust. Electrophysiological and neural imaging studies are revealing taste's neural organisation. The weight of evidence implies that reflexive responses to tastants are orchestrated in the hindbrain, that a cognitive analysis of taste quality and intensity is completed in primary taste cortex, and that the reward value of a taste is added in secondary taste cortex and in ventral forebrain areas. Taste signals are also integrated with those from touch, smell, vision and the viscera to compose a sense of flavour.

Key Concepts:

The taste system protects us from ingesting toxins through rejection reflexes and a sense of disgust; it encourages us to consume nutrients through swallowing reflexes and a sense of pleasure.

A cognitive identification of taste is most likely made in primary taste cortex in the insula.

Taste information is integrated with that from other senses in cortical and ventral forebrain areas to create a sense of flavour.

Taste and flavour are imbued with hedonic tone – pleasure or disgust – in orbitofrontal cortex and ventral forebrain.
Anaerobes
Authors: Oren Aharon
Published: April 2013

A diverse world of microorganisms inhabits anaerobic environments on Earth, and these obtain their energy by fermentation or by anaerobic respiration, in which electron acceptors other than molecular oxygen drive the oxidation of organic compounds. We also know phototrophic and chemoautotrophic processes that function in the absence of oxygen. Collaboration of different groups of microorganisms can lead to degradation of complex organic matter also under anaerobic conditions, with carbon dioxide or a mixture of carbon dioxide and methane as the main products, depending on the availability of electron acceptors other than molecular oxygen, such as nitrate or sulfate. The different groups of anaerobes are essential for the functioning of the biogeochemical cycles of carbon, nitrogen, sulfur and other elements, and also play important roles in the production of fermented food products, treatment of organic wastes and other biotechnological processes.

Key Concepts:

Life developed on planet Earth in the absence of molecular oxygen (O
2
).

The anaerobic way of life is widespread in the prokaryotic world – in Bacteria as well as Archaea.

Permanently anaerobic environments include marine and freshwater lake bottom sediments, digestive systems, the deep subsurface and others.

Some protozoa can live anaerobically.

Recently a community of multicellular meiozoa that lives in permanently anoxic conditions was discovered in L'Atalante basin, 3.5 km below the surface of the Mediterranean Sea.

In the absence of molecular oxygen, many prokaryotes can use alternative electron acceptors, such as nitrate, sulfate, Fe(III) and others, for respiration (‘anaerobic respiration’).

When no suitable electron acceptor is available, energy can be gained by fermentation processes, in which ATP is gained by substrate‐level phosphorylation.

Complete anaerobic breakdown of organic matter is a cooperative process in which fermentative microorganisms, bacteria performing anaerobic respiration and methanogenic Archaea cooperate.

Hydrogen and acetate are key intermediates in many anaerobic degradation processes.
Biofuels: Microbially Generated Methane and Hydrogen
Authors: McAnulty Michael J , Vepachedu Venkata R , Wood Thomas K , Ferry James G
Published: April 2013

The production of methane (CH
4
) or hydrogen (H
2
) from renewable biomass by microorganisms growing anaerobically has the potential for contribution to independence from fossil fuels. Anaerobes function in Nature by converting biomass to CH
4
through food chains comprised of fermentative and acetogenic species, which decompose the complex biomass to H
2
, formate and acetate that are further metabolised to CH
4
by methanogens. Methanogens reduce the concentration of products to levels that permit the initial decomposition of biomass by fermentative and acetogenic species. Current H
2
production relies extensively on energy‐intensive fossil fuel sources. Photosynthetic and fermentative species offer more efficient routes for H
2
production. Although fermentatives have significantly higher production rates, they have lower yields of H
2
but may be a source of other valuable compounds that are synthesised along with H
2
. Further research must be conducted on obtaining H
2
from reductive pools of NAD(P)H to increase yields and increase economic competitiveness.

Key Concepts:

Methane production from biomass, an essential component of the global carbon cycle, requires a microbial food chain.

Methane‐producing species (methanogens) are terminal organisms of the food chain metabolising acetate, formate and H
2
that are metabolic products of species initiating decomposition of the biomass.

The methyl group of acetate is reduced to methane with electrons derived from oxidation of the carbonyl group.

Carbon dioxide is reduced to methane with electrons derived from oxidation of H
2
or formate.

Current hydrogen production relies on fossil fuel sources.

Photosynthetic hydrogen production yields are high, but rates are slow.

Dark hydrogen production rates are fast, but yields are low.

Higher yields through dark fermentation may be obtained using pathways that use NAD(P)H.

Additional products such as 1,3‐propanediol and ethanol may be obtained along with hydrogen in dark fermentations.
Water Transport Across Cell Membranes
Authors: Reuss Luis
Published: April 2013

This chapter is focused on the pathways and molecular mechanisms of water transport across the plasma membrane of animal cells. We discuss basic principles of water transport, including diffusion and osmosis and apply these concepts to the case of cell‐membrane water transport. The general conclusion is that diffusion and osmosis can explain water transport and that other mechanisms (e.g. cotransport) are less likely. Concerning the pathways for water movement across the plasma membrane, we consider the lipid bilayer, water‐selective pores (aquaporins – AQPs), nonselective larger pores, ion channels and membrane carriers. We conclude that the lipid bilayers and AQPs are the main pathways for transmembrane water fluxes, by solubility–diffusion and single‐file transport, respectively. Cell‐membrane water permeability varies considerably from cell to cell; high permeability denotes a fluid lipid bilayer and expression of AQPs. Low water permeability occurs when there is no aquaporin expression and membrane is rich in cholesterol.

Key Concepts:

Water transport across cell membranes occurs bydiffusionandosmosis.

Theeffective osmolalityof a biological fluid is determined by the total solute concentrations and the solutes’ permeabilities, relative to water.

The cell‐membrane osmotic water permeability varies from cell to cell, depending on the composition of the lipid bilayer and the presence or absence of water pores.

The two main pathways for plasma‐membrane water transport are the lipid bilayer and water‐selective pores (aquaporins).

Aquaporins are a large family of water pores; some isoforms are water‐selective whereas others are permeable to small solutes.

Aquaporin 1 (AQP1), the best studied isoform, is present in the membrane as a tetramer; each monomer has a water pore.

The pore of AQP1 is long and narrow (c. 2.8 Å diameter); water molecules lose their hydrogen bonds and permeate in single file.

AQP‐mediated water permeability appears to be regulated mostly by controlling the number of molecules present in the membrane. Regulation of the ‘opening’ of the pores has also been proposed for some isoforms.

AQP1 genetic deletion in mice causes profound alterations of renal function, consistent with a major physiological role of this protein.
Genetics and the History of the Basque People
Authors: López Saioa , Alonso Santos
Published: April 2013

The biological research on the origins of the Basque people was strongly motivated by the singularity of their language. Early investigations based on comparative craniometrics go back to the nineteenth century. These suggested the idea of a local evolution for the Basques. However, this approach soon proved to be unreliable. In the mid‐twentieth century, classical markers seemed to confirm that Basques were descendants of local Mesolithic Europeans who had avoided the impact of Near East Neolithic farmers better than other European populations.
Deoxyribonucleic acid
(DNA) typing and recent genome‐wide studies have allowed a more realistic reconstruction of the evolutionary history of populations. Further implications emerge from the genetic analysis of human remains from ancient archaeological sites. Several lines of evidence indicate that at least some Basque DNA lineages have evolved

in situ

, probably since pre‐Neolithic times. However, the place of the Basques in the European diversity landscape is still far from being completely elucidated.

Key Concepts:

Since mid‐twentieth century it has been speculated that Basques were descendants of local Mesolithic Europeans who had avoided the impact of Near East Neolithic farmers.

Traits under the influence of the environment are not reliable approaches to infer the evolutionary origins of populations. These include craniometrics and blood groups.

At least some Basque DNA lineages might have evolved
in situ
, probably since pre‐Neolithic times.

Evolutionary inferences made from modern DNA make substantial simplifications of human demographic history. Ancient DNA analysis can provide a clearer picture of our past and can enhance our chances to reconstruct our history.

The singularity of the Basques in the European diversity landscape is still controversial. Genetic heterogeneity within Basques is a possible confounder.