bluuebunny/crossref_metadata_2025 huggingface dataset:
The Basic Science of Addiction
Authors: Melendez Roberto I , Kalivas Peter W
Published: November 2023

Drug addiction can be defined as a chronically relapsing behavioral disorder characterized by compulsive, at times uncontrollable, drug craving, seeking, and use that persists even in the face of negative consequences (O’Brien, 2001). Addictive drugs produce their behavioral effects by initiating a cascade of neurochemical events that ultimately makes the organism seek the drug. Thus, addictive drugs have the property of reinforcing or rewarding drugrelated behaviors and thereby increasing the probability of a response, which is core to our understanding of the behavioral attributes associated with addiction.
Neurobiology of Opioids in Dependency
Authors: Perrotti Linda I
Published: November 2023

Opiates exert their rewarding effects though actions at µ-opioid receptors (MOR) in the ventral tegmental area (VTA) in the midbrain. Activation of MOR disinhibits GABA neurons, which ordinarily hold VTA dopaminergic neurons in abeyance. This disinhibition increases the release of dopamine (DA) to the major target of the VTA dopaminergic cells, the nucleus accumbens (NAc), as well as other regions of the limbic forebrain. Chronic exposure to opiates results in neural adaptations that lead to tolerance, sensitization, and dependence.
Alcohol Use Disorders and Their Treatment
Authors: Flannery Howard S Smith Mary Jeanne Kreek Carrie L Johnson Kenneth L , Newlin David
Published: November 2023

Alcohol dependence is a chronic, relapsing disorder of the brain (Leshner, 1997, p. 45). It is in this sense similar to dependence/ abuse of other drugs and for that matter to most other psychiatric illnesses. Alcohol use disorders (AUDs, which include alcohol dependence and alcohol abuse) are complex diseases that have substantial heritable components ranging from 40% to 60%, which allows for major environmental aspects of their etiologies. Although AUDs appear to be polygenic with many small, additive gene effects, important epistatic (gene-gene interactions) and geneenvironment interactions cannot be ruled out at the present time. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision (DSM-IV-TR; American Psychiatric Association, 2000) is the de facto standard for diagnosing AUDs. The criteria for alcohol abuse include significant problems associated with alcohol and persistent use despite these problems, hazardous use (e.g., intoxicated driving), and/or recurrent legal problems. Importantly, alcohol abuse is diagnosed when the criteria for alcohol dependence have not been met. Alcohol dependence involves a constellation of symptoms associated with significant impairments that include marked tolerance to alcohol’s intoxicating effects, withdrawal symptoms, escalating use despite problems, inability to limit use, and/or preoccupation with alcohol.
Smoking, Pain, and Addiction
Authors: Dhingra Lara K , Ostroff Jamie S
Published: November 2023

Smoking rates among adults with persistent pain are high (30%– 64%) compared to the general population (22%). Smokers with persistent pain are likely to be more nicotine dependent and have difficulty quitting smoking. Further, smokers with persistent pain have higher rates of opioid abuse compared to nonsmokers with pain. Smokers with more severe nicotine dependency are more likely to misuse their opioid medications than smokers with lower nicotine dependency. Despite these findings, smoking is an underappreciated risk and poorly understood factor for opioid therapy and functional rehabilitation in pain management. Thus, examining the link between smoking and aberrant drug-taking behavior is critical to clinicians and researchers seeking to understand a patient’s potential risk for prescription opioid abuse.
Opioid Pharmacology for Pain
Authors: Inturrisi Charles E
Published: November 2023

The increased availability of opioid maintenance treatment through office-based practice means that many chemically dependent individuals will require pain management in a primary care setting (Alford et al., 2006). This management will include the use of opioid analgesics because these drugs remain the most effective and commonly used modality for the alleviation of moderate to severe pain (Inturrisi, 2002). The issues, problems, and approaches that are to be used for pain management in chemically dependent patients, regardless of the setting, are discussed through-out this volume. The purpose of this chapter is to focus on the pharmacological properties of opioids that form the basis for their use in pain management. The most effective use of these drugs requires consideration of these properties regardless of whether or not the patient in pain is chemically dependent.
Behavioral Medicine Approaches to Pain Management
Authors: Okifuji Akiko
Published: November 2023

Chronic pain is one of the most prevalent physical conditions accounting for long-term disability (Von Korff et al., 2005). Unlike transitory or acute pain that either remits spontaneously or responds to fairly simple intervention, chronic pain persists beyond an expected period for which healing of the initial injury completes despite treatments. The average duration of pain noted for patients treated at clinics specializing in the treatment of chronic pain typically exceeds 7 years with pain duration of 20 to 30 years (Flor, Fydrich, Turk, 1992).
Support Groups and Twelve-Step Programs in the Treatment of the Chronic Pain Patient
Authors: Ziedonis Douglas M , Berman Jeffrey A , Lehn M Dale , Colameco Stephen
Published: November 2023

Chronic pain can cause great emotional and spiritual suffering, including isolation, exaggerated fears, obsession, shame, guilt, irrational thinking, anger, resentment, self-pity, and confusion. Patients often struggle with the question, ‘‘Why me?’’ Medication management, behavioral therapy, and complementary treatment approaches are commonly used and are often effective in helping the individual manage chronic pain; however, some individuals are better able to manage their chronic pain because they receive additional support and anticipatory guidance from peers at chronic pain support and 12-step groups.
Chemical Coping The Clinical Middle Ground
Authors: Passik Steven D , Kirsh Kenneth L
Published: November 2023

Pain clinicians recognize that there is a vast middle ground between generally compliant drug-taking behavior on the one hand and frequent/severe aberrant behaviors that are likely to be associated with addiction on the other (see Figure 35.1). Compliant drug-taking behavior is usually associated with opioid therapy that is beneficial to the patient, whereas frequent and severe aberrant behavior is generally associated with opioid exposure that is potentially harmful to the patient. There is a large group of patients in the middle: those who display aberrant behaviors periodically, who may additionally have a mixed response to opioid therapy, the overall results of which are less than satisfying (often in the domain of functionality).
Documentation and Potential Documentation Toolsin Long-Term Opioid Therapy
Authors: Kirsh Kenneth L Howard S , Smith Howard S
Published: November 2023

The use of long-term opioid therapy (LTOT) to treat chronic nonmalignant pain is growing, based in part on evidence from clinical trials and a growing consensus among pain specialists (Collett, 1998; Portenoy, 1996a, 1996b; Urban et al., 1986; Zenz et al., 1992). The appropriate use of these drugs requires skills in opioid prescribing, knowledge of addiction medicine principles, and a commitment to perform and document a comprehensive assessment repeatedly over time. Inadequate assessment can lead to undertreatment, compromise of the effectiveness of therapy when implemented, and prevention of an appropriate response when problematic drug-related behaviors occur (JCAHO, 1999; Katz, 2002; Max et al., 1999).
Closing Thoughts
Authors: Wittry Diane
Published: November 2023

It is important always to be learning as a conductor. Often, we think that study- ing new repertoire is the only learning we need, but that is just the tip of the ice- berg. Of course, you want to be constantly exposing yourself to new music and investigating lost works and composers, but you also need to grow in many other ways. Often, as conductors, we stop attending concerts because we are spending so much time conducting our own that going to others feels like work. Try not only to keep attending quality concerts at which you can observe top conductors in the field but also make it a point to attend rehearsals. Most orchestras are very open to this.
Introduction
Authors: Vaget Hans Rudolf
Published: November 2023

The literary fortunes of Thomas Mann’s 1924 novel The Magic Mountain in the English-speaking world, unlike those in his native country, have been rather mixed. Looking back over the eighty years since its publication, we can readily distinguish three phases in the critical reception of the book: first, a period of widespread acclaim, in which The Magic Mountain was generally held in the highest regard; second, a period of benign neglect in which the novel receded into the background of the literary landscape; and third, during the last two decades a period of significant new interest in Mann’s work.
The Making of The Magic Mountain
Authors: Vaget Hans Rudolf
Published: November 2023

Ashort time after the publication of Doctor Faustus in 1948, Thomas Mann began to write The Story of a Novel: The Genesis of Doctor Faustus, a book that lays out the biographical and historical context from which the novel sprang, covering the period from May of 1943 to February of 1947. Mann had an excellent and compelling reason to rehearse the composition of Doctor Faustus and to make his account public. He wanted to acknowledge the contribution to his work of Theodor W. Adorno, the philosopher and theoretician of the twelve-tone method of musical composition advanced by Arnold Schoenberg and his followers, and thereby nip in the bud a clear and present danger—that Adorno might one day raise the issue of intellectual property, just as Schoenberg him-self had done after the publication of the novel when he accused the author of Doctor Faustus of having appropriated the invention of dodecaphonic music and of having misleadingly attributed it to his fictional hero, the composer Adrian Leverkühn. Similar issues of mimesis had been dogging Mann from the time of Buddenbrooks. As we shall see, they acquired a new and special virulence with The Magic Mountain.
Death, Knowledge, and the Formation of Self :The Magic Mountain
Authors: Travers Martin
Published: November 2023

The experience of death is central to all of Mann’s early fiction, from Buddenbrooks (1901) through to Death in Venice (1912). Tonio Kröger is the only major work of this period in which that experience is absent; in all of Mann’s other works, death appears either as a brute reality, the inevitable culmination of physical decline, or, more metaphysically, as the object of longing, a solution to the crisis of alienated sensibility that besets many of Mann’s early “heroes,” from little Herr Friedemann (in the short story of that name) through to Hanno Buddenbrook. To a large extent, this preoccupation with death arises, quite logically, out of the themes that Mann addressed in this early body of work: the relationship between knowledge and sickness, between attenuated sensibility and decadence, and the plight of the artist torn between bourgeois happiness and artistic vocation.
The “Magic Mountain Malady”: Der Zauberberg and the Medical Community, 1924–2006
Authors: Herwig Malte
Published: November 2023

For more than eighty years, Thomas Mann’s 1924 tale of life, disease, degeneration, and death has both fascinated the general reader and con-spicuously exercised the imagination of the medical professional. Indeed, not only has this novel become a classic of twentieth-century fiction but after an initially skeptical reception by the medical community it has been enshrined in the canon of literary works that have become required reading for aspir-ing physicians.
The Moral Significance of Early Human Embryos in Secular Thought
Authors: Cohen Cynthia B
Published: November 2023

The dream of scientists and many patients of using human embryonic stem cells to treat the seriously ill has been interrupted by the alarmed voices of those who see human embryos as vulnerable living humans. These objectors do not reject stem cell research in itself, for they recognize that it may offer new forms of treatment and insights into human development. Instead, they reject human embryonic stem cell research because it necessarily involves the destruction of early human embryos. To destroy human embryos, these objectors declare, is to destroy individual living human beings and is therefore wrong.

Others, however, take different views of the moral significance of early human embryos. These range from the view that they do not have the potential to produce individual humans until after fourteen days of growth to the position that they are insignificant groups of human cells. Although these other commentators start from different positions, they reach the same conclusion: early human embryos at five to six days of growth are not individual human beings, and their use in embryonic stem cell research can be morally justifiable.
The Development of National Policy on Stem Cell Research in the United States
Authors: Cohen Cynthia B
Published: November 2023

Stem cell research was being carried out in a fairly low-key way by scientists in various parts of the world until 1998, when news of the isolation and cultivation of human embryonic stem cells burst onto the national scene. Public, scientific, and legislative interest in this novel and promising research surged immediately around the world. The question whether it should proceed with federal support in the United States became the subject of explosive debate in the halls of Congress and among members of antiabortion groups and patient advocacy organizations, as well as the general public.

President William J. Clinton responded affirmatively to this question and was poised to allow federal funding of research with human embryonic stem cells when the George W. Bush administration came into office in 2000. The new president initiated a more restrictive policy regarding such research than the Clinton administration had planned, allowing it to proceed with federal funding on a limited number of human embryonic stem cell lines. Bush continued to provide federal support for research on adult stem cells and stem cells found in umbilical cords, placental blood, and bone marrow.
Parasomnias and Abnormal Sleep-Related Movements
Authors: Lee-Chiong Teofilo
Published: November 2023

Parasomnias are undesirable physical phenomena or behavior that develop during the sleep period. These abnormal events or experiences are not principally abnormalities of the states of sleep and wakefulness, and they are not generally associated with major complaints of excessive sleepiness or insomnia. Parasomnias can manifest as activation of skeletal muscles or the autonomic nervous system during sleep. They usually occur intermittently or episodically either within sleep or during its transition to and from wakefulness. Occasionally, parasomnias may give rise to violent and potentially injurious behavior.

Parasomnias can be classified into three groups based on the American Academy of Sleep Medicine International Classification of Sleep Disorders (ICSD; second edition; see References) (Box 7–1).

1. Disorders of arousal from non–rapid eye movement (NREM) sleep, including confusional arousals, sleepwalking, and sleep terrors

2. Parasomnias usually associated with rapid eye movement (REM) sleep, including REM sleep behavior disorder (including parasomnia overlap disorder and status dissociatus), recurrent isolated sleep paralysis, and nightmare disorder

3. Other parasomnias, including sleep-related dissociative disorder, sleep enuresis, sleep-related groaning (catathrenia), exploding head syndrome, sleep-related hallucinations, and sleep-related eating disorder.
Linguistics In The Courtroom
Authors: Shuy Roger W
Published: November 2023

This is a practical guide for both beginning and established linguists who have been asked by lawyers to address the language issues in their civil and criminal cases. Author Roger W. Shuy deals with issues of how to become an expert, how to start and manage a practice of consulting on law cases, how to address the issue of professional ethics, how to work with lawyers, write reports, affidavits, and participate successfully in depositions, direct examination, and cross examination at trial. The book also suggests ways that linguists can use their forensic linguistic experiences in their publications and classroom teaching, along with suggestions of recent books that forensic linguists may need for their personal libraries.
Human Malformations and Their Genetic Basis
Authors: Epstein Charles J
Published: November 2023

Of the many problems encountered in the practice of clinical genetics, perhaps the most perplexing, in terms of understanding pathogenesis, have been the conditions characterized by the presence of congenital malformations. Winter (1996) estimated that approximately 1 in 40 (2.5%) newborns has recognizable congenital abnormalities at birth. These occur half the time as single malformations and half the time as multiple malformations. It has also been estimated that of the more than 1750 inherited human disorders that result in altered morphogenesis, more than 1000 are multiple malformation syndromes (Wilson, 1992).
Development of the Vascular System
Authors: Barnes Carmen M , Christison-Lagay Emily R , Huang, Sui , Kaipainen Arja
Published: November 2023

The formation of the vascular system is one of the earliest events of embryogenesis occurring shortly after implantation. Its formation not only provides a network by which the developing embryos receive oxygen and nutrients but also the cells of vascular origin themselves produce instructive trophic factors that promote organogenesis (reviewed by Risau, 1997; Yancopoulos et al., 1998).
The Development of Bone and Cartilage
Authors: Murakami Shunichi , Akiyama, Haruhiko , Crombrugghe Benoit De
Published: November 2023

The formation of bone occurs through two distinct mechanisms. More than 95% of the skeleton is formed by the complex process of endochondral ossi7cation, which involves a cartilage intermediate. The other bones, namely some craniofacial bones, are formed directly from the condensations of mesenchymal cells without cartilage intermediate, a process described as intramembranous ossi7cation. Bones contain both bone-forming osteoblasts, which arise from mesenchymal cells, and bone-resorbing osteoclasts, which arise from macrophage/ monocytic cells. The coexistence of the two cell types insures bone homeostasis, which is the result of a functional steady-state characterized by an equilibrium between bone synthesis and bone resorption. In cartilage, a single cell lineage, represented by different subpopulations of chondrocytes, constitutes the only cell type of this tissue. Cartilage in articular surfaces, which line the extremities of many bones, and cartilage in the nose, ears, and throat are never replaced by bone and persist as permanent cartilage. It is not clearly understood why chondrocytes in such cartilage do not develop into bone.
Development of the Endodermal Derivatives in Lung, Liver, Pancreas, and Gut
Authors: Stanger Ben Z
Published: November 2023

The derivatives of endoderm display an extraordinary diversity of function, including gas exchange, digestion, nutrient absorption, detoxi7cation, and endocrine regulation. A wide range of developmental disorders is attributable to the abnormalities of endoderm function, corresponding to the steps that normally give rise to these tissues. These include (1) endoderm formation (gastrulation) and spatial speci7cation (patterning), (2) physical formation of the primitive organ anlagen (budding), (3) shaping of tissue architecture (morphogenesis), and (4) creation of speci7c functional cell types within the organ (differentiation). This chapter reviews the development of the lung, liver, pancreas, and gut, focusing on the molecular determinants of each of these processes.
GLI3 and the Pallister–Hall and Greig Cephalopolysyndactyly Syndromes
Authors: Biesecker Leslie G
Published: November 2023

Pallister–Hall syndrome (PHS) and Greig cephalopolysyndactyly syndrome (GCPS) are distinct, pleiotropic developmental anomaly syndromes that are caused by mutations in GLI3 and inherited in an autosomal dominant pattern. The major anomalies in PHS include hypothalamic hamartoma, central or postaxial polydactyly, and airway anomalies. The major anomalies of GCPS include macrocephaly with hypertelorism and preor postaxial polydactyly. Both disorders have a wide spectrum of severity but are clinically distinct. The GLI3 gene encodes a C2H2-type zinc 7nger transcription factor that is downstream in the sonic hedgehog (SHH) signaling pathway. The mutational spectrum of GLI3 mutations in patients with GCPS is broad, including translocations, gross and molecular deletions, amino acid substitutions, and frameshift and nonsense mutations. The mutational spectrum of PHS typically comprises only frameshift mutations that preserve the zinc 7nger binding domain of GLI3. A hypothesis has been proposed to explain the correlation of these two phenotypes and the associated mutations.
WISP3 and Progressive Pseudorheumatoid Dysplasia
Authors: suwairi Wafaa , Warman matthew L
Published: November 2023

Mutation in Wnt-1 inducible signaling pathway protein 3 (WISP3) (CCN6), a member of the CCN (CTGF, CEF10/Cyr61, Nov, and, now, WISP1, WISP2, and WISP3) family of secreted growth regulators causes the autosomal recessive disorder progressive pseudorheumatoid dysplasia (PPD) (Hurvitz et al., 1999). Of the six members of the CCN gene family, only WISP3 has been associated with a human Mendelian disease phenotype. The precise developmental pathway by which WISP3 causes disease is unknown. The ability to regulate diverse pathways [e.g., bone morphogenetic protein, Wnt, transforming growth factor-β (TGF-β), Integrin, and insulin-like growth factor 1 (IGF1)] has been identi3ed among CCN family members. However, most activities have been identi3ed ex vivo or using nonphysiologic levels of messenger RNA (mRNA)/protein in vivo. Consequently, the roles of Wisp3 and the other CCN family members in the physiologic, in vivo, regulation of developmental and homeostatic pathways require further investigation.
AXIN2, Tooth Agenesis, and Colorectal Cancer
Authors: Nieminen Pekka , Lammi, Laura , Järvinen Heikki J
Published: November 2023

Mutations in the human AXIN2 gene cause dominantly inherited tooth agenesis with severe but variable phenotype. At the same time, they predispose to colorectal cancer. The role of AXIN2 as a regulator of Wnt (wingless)-signaling is in line with the well-established role of deregulated β-catenin activity in promoting colon cancer. However, while for tooth agenesis the underlying pathogenesis is less obvious, this finding highlights the importance of signal regulation for organogenesis. As genetic background for tooth agenesis, one of the most common developmental anomalies in man, is still largely unknown, it will be interesting to find whether other connections between tooth agenesis and cancer predisposition will be identified.
AMH/MIS and Its Receptors: The Persistent Müllerian Duct Syndrome
Authors: Picard Jean-Yves
Published: November 2023

Antimüllerian hormone (AMH), also called müllerian inhibiting substance (MIS), is a member of the transforming growth factor-β (TGF-β) family, produced exclusively by the gonads, that plays an important role in sex differentiation and gonadal function.
TWIST1 and the Saethre–Chotzen Syndrome
Authors: Jabs Ethylin Wang
Published: November 2023

Saethre–Chotzen syndrome (OMIM 101400) is one of the most common craniosynostosis syndromes with autosomal dominant inheritance. The most frequently observed features are the premature fusion of coronal sutures resulting in brachycephaly, low frontal hairline, facial asymmetry, ptosis of the eyelids, prominent helical crus, syndactyly, and broad great toes. This syndrome is caused by mutations in the TWIST1 gene that map to chromosome 7p21 and codes for a basic helix–loop–helix (bHLH) transcription factor (OMIM 601622). At least 97 different mutations, including missense and nonsense changes, small insertions and deletions leading to frameshifts, and duplications, have been identified in patients. These mutations lead to loss of the ability of the HLH domain to dimerize or the basic region to bind to its target(s). Loss of the entire gene and potential regulatory elements as far away as a few megabases from the coding region of TWIST1 can also cause the Saethre–Chotzen syndrome phenotype. Chromosomal rearrangements or deletions involving the 7p21-p22 region are more often found than intragenic mutations in patients with mental retardation. Twist1 heterozygous null mice with craniofacial and limb abnormalities that resemble Saethre–Chotzen syndrome further support loss of function as the mechanism by which mutant TWIST1 leads to the phenotype. Previously, patients with Saethre–Chotzen-like features and duplication of the great toe or radial ray hypoplasia were diagnosed as having separate clinical entities, Robinow–Sorauf or Baller–Gerold syndrome, respectively. These patients also have TWIST1 mutations and are now thought to represent phenotypic variability in the Saethre– Chotzen syndrome. Normally, TWIST1 has an inhibitory role in osteoblast and myocyte differentiation which is mediated through targets such as histone acetyltransferase, cell cycle regulators, and cytokines. Thus, loss of this inhibitory effect in Saethre–Chotzen syndrome leads to increased osteoblast proliferation, decreased differentiation, and apoptosis resulting in synostosis at cranial sutures and abnormalities of limb development. Potential modifiers of the effect of TWIST1 mutations include interacting proteins and components of several developmental pathways including the bHLH proteins TWIST2, SNAI1, SNAI2, ID1, and HAND2; transcription factors RUNX2, MSX2, and ALX4; and fibroblast growth factor receptors (FGFRs). Selection of dimer partners and posttranslational modification are additional mechanisms by which the severity of craniosynostosis and limb anomalies are modulated in Saethre–Chotzen syndrome.
Introduction to Notch Signaling
Authors: Miyamoto Alison , Weinmaster Gerry
Published: November 2023

During the earliest stages of embryogenesis, >ve signaling pathways direct the majority of developmental decisions: Wnt, TGF-α, Hedgehog, RTK, and Notch (Gerhart, 1999). Consistent with Notch signal transduction regulating a wide variety of cell types during specication, patterning, and morphogenesis, mutations in Notch signaling elements are causative in a number of human diseases (Hansson et al., 2004), some of which will be discussed in the following chapters.
NF1 and Neurofibromatosis 1
Authors: Daginakatte Girish C , Gutmann David H
Published: November 2023

Neurofibromatosis 1 (NF1, OMIM 162200) is a common genetic disorder with an estimated prevalence of approximately 1 in 3500, regardless of gender, ethnic background, or race (Friedman, 1999). It is transmitted in an autosomal dominant inheritance pattern with complete penetrance, but variable expressivity.
HOXD10 and Congenital Vertical Talus
Authors: Shrimpton Antony E , Levinsohn E Mark
Published: November 2023

Congenital vertical talus (CVT), also known as “rocker bottom foot” deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This dislocation results in a characteristic radiographic vertical orientation of the talus. This condition is usually associated with multiple other congenital deformities (e.g., myelomeningocoele neuromuscular syndromes, and aneuploidies) and only rarely as an isolated deformity (Hamanishi, 1984). An identical mutation, a recurrent missense mutation (M319K; 956T>A) in the HOXD10 transcription factor gene, is the only mutation so far identified in autosomal dominant isolated CVT families. In one family, it had variable expression, manifesting in a Charcot-Marie-Tooth (CMT)-like pes cavus claw toe appearance in a minority of carriers. The finding of M319K, twice, in isolated CVT families implies a specific dominant gain of function disease mechanism. To date, no mutations have been identified in nonfamiliar isolated CVT cases.
EYA1 and the Branchio–Oto–Renal Syndrome
Authors: Alkuraya Fowzan S , Moy, Robert T , Maas Richard L
Published: November 2023

Mutation of Eyes Absent 1 (EYA1) is an established cause of Branchio–Oto–Renal (BOR) syndrome (OMIM 113650). EYA1, the EYA1 gene product, which belongs to a highly conserved family of transcriptional coactivators that are recruited along with members of the Six family of homeoproteins to specific enhancers. EYA1 also encodes a novel protein phosphatase function. Thus, EYA1 heterozygosity is thought to underlie the BOR phenotype through impairment of either or both functions. The resultant phenotype typically includes deafness with associated otic, renal, and branchial abnormalities, although highly variable expressivity often means that all three BOR characteristics are rarely found in a single patient. Thus, EYA1 mutation can also result in the simpler Branchio–Oto (BO) syndrome. Not surprisingly, mutation in the SIX1 gene that encodes a molecular interactor with the EYA1 protein can also cause BOR and BO syndromes.
NKX2-5 and Congenital Heart Disease
Authors: Gazit Avihu Z , Foerster, Susan N , Jay Patrick Y
Published: November 2023

Nkx2-5 is a homeodomain-containing transcription factor that is required for normal embryonic cardiac development (see Chapter 10). Loss of the homologous gene tinman in Drosophila results in absence of the dorsal vessel, the %y equivalent of the heart. A homozygous null mutation of Nkx2-5 in mouse causes arrest of cardiac development during looping of the heart tube and embryonic lethality. The heterozygous null mutation in mice replicates some of the defects observed in humans. The )rst reported patients had a familial syndrome of atrial septal defect (ASD) and atrioventricular (AV) conduction block. Additional mutations have been discovered in a wide range of congenital heart defects, including ventricular septal defect (VSD), tetralogy of Fallot, hypoplastic left heart syndrome, and Ebstein malformation of the tricuspid valve. Mutations of Nkx2-5 are also associated with deleterious effects on cardiac rhythm and function in some patients. The diagnosis and management of such patients are discussed. Finally, mouse models and biochemical experiments suggest that developmental pathogenesis involves numerous molecular interactions between Nkx2-5, modi)er genes, other transcription factors, and gene-regulatory sequences. The many interactions and subtle hemodynamic variables likely in%uence the spectrum of cardiac phenotypes associated with Nkx2-5 mutations.
FOXC2 and Lymphedema Distichiasis
Authors: Erickson Robert P
Published: November 2023

ymphedema distichiasis (LD) is a dominantly inherited syndrome of high penetrance and extremely variable expression. Its most constant feature is distichiasis, a double row of eyelashes due to secondary eyelashes growing from the meibomian glands. Lymphedema is typical of adolescent onset but can be so severe as to cause hydrops fetalis and may not appear at all. LD results from heterozygosity for null mutations at FOXC2. FOXC2 is a member of the forkhead transcription factor family. This gene family codes for transcription factors with both positive and negative effects on transcription. The pattern of embryonic expression of Foxc2 and the phenotype of homozygous nulls predict the extra clinical features seen in LD: cleft palate, cardiac abnormalities, extradural spinal cysts, and ptosis. To date, only 4 of 49 published mutations have been missense, strongly suggesting that it is haplode&ciency, which results in the phenotype.
RSK2 (RPS6KA3) and the Coffi n–Lowry Syndrome
Authors: Zeniou Maria , Jacquot Sylvie , Delaunoy, Jean-Pierre , Hanauer Andr
Published: November 2023

loss-of-function mutations in the gene encoding the protein kinase ribosomal S6 serine/threonine kinase 2 (RSK2) are responsible for Coffin–Lowry syndrome (CLS; OMIM 303600), a syndromic form of X-linked mental retardation. Cardinal features of CLS are growth and psychomotor retardation, characteristic facial and digital abnormalities, and progressive skeletal deformations.
IRF6 and the Van der Woude Popliteal Pterygium Syndromes and the Risk for Nonsyndromic Cleft Lip and Palate
Authors: Schutte Brian C , Dixon, Michael J , Murray Jeffrey C
Published: November 2023

Van der Woude syndrome (VWS; OMIM 119300) is a highly penetrant, autosomal dominant orofacial clefting disorder. VWS is characterized by clefts of the lip and/or palate with accompanying paramedian lower lip pits. An allelic variant, the popliteal pterygium syndrome (PPS), includes additional features of lower extremity pterygia, genital anomalies, skin overlapping the great toe, and other occasional features. Mutations in the transcription factor interferon regulatory factor 6 (IRF6) account for most cases of VWS/PPS with limited evidence for locus heterogeneity. Although VWS and PPS are relatively rare disorders, common variants in IRF6 also contribute to isolated cleft lip and palate. Isolated cleft lip and palate is a common birth defect with a prevalence of approximately 1 per 1000 live births. Thus, IRF6 is a critical component of the molecular cascade driving development of the lip and palate. Gene expression studies and mouse models are now providing additional insights into the role of this gene and others in the IRF6 developmental pathway in both facial and epithelial development.
Posttranscriptional Control: Nuclear RNA Processing
Authors: SWANSON MAURICE S , ARIS JOHN P
Published: November 2023

Normal development of human tissues requires the activation of specific genes during various embryonic stages so that stage-specific protein isoforms and other gene products appear in their proper developmental windows. While transcriptional initiation starts the gene expression cascade, nascent transcripts must be modified and the mature RNA products correctly localized within the cell. Most of the nuclear processing machinery is devoted toward producing the major RNAs required for the translational apparatus (Fig. 125–1). Pre-messenger RNAs (pre-mRNAs) are transcribed by RNA polymerase II (Pol II) and modified (capped) at the 5′ end by 7-methylguanosine, introns are removed by the spliceosome and the mature 3′ ends of mRNAs are generated by endonucleolytic cleavage which is generally followed by polyadenylation. Ribosomes begin life in the nucleolus where pre-ribosomal RNA (pre-rRNA) processing involves a series of nucleolytic cleavage steps as well as nucleotide modifications which results the synthesis of subunit precursors. These precursors are subsequently exported into the cytoplasm for the final modification steps required to form functional subunits. A similar biogenesis pathway is followed by pre-transfer RNAs (pre-tRNAs) although the majority of these processing events occur outside of the nucleolus. Overall, the cell expends an enormous amount of metabolic energy on these RNA processing and localization pathways. Recent estimates suggest that the spliceosome alone may be composed of hundreds of protein factors in addition to the five small nuclear RNAs (snRNAs) (Jurica and Moore, 2003). Mutations in any one of these factors, or the cis-acting elements to which they bind, may result in human disease.
UBE3A and the Angelman Syndrome
Authors: Rayburn Lowell , Wagstaff Joseph
Published: November 2023

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of the ubiquitin-protein ligase UBE3A in the brain.

The genetic pathogenesis of AS is complex, because the UBE3A gene shows parent-specific differential expression, or imprinting, limited to the brain. In most tissues, the maternal and paternal alleles of UBE3A are expressed equally; in some brain regions, however, the maternal allele is expressed at a much higher level than the paternal allele. AS results from any of a number of genetic mechanisms that lead to absence of a functional allele of UBE3A inherited from the mother; absence of a functional paternal allele of UBE3A causes no phenotypic effects. The protein product of UBE3A, also known as E6-AP (E6-associated protein), was first identified as a cellular protein that forms a complex with the E6 proteins of high-risk human papillomaviruses (HPVs); this complex ubiquitinates the p53 tumor suppressor, thereby targeting it for degradation by the proteasome. In normal human tissues, however, p53 does not appear to be a UBE3A substrate. The substrate(s) of UBE3A that fail to be ubiquitinated in the brains of AS patients, and that lead to the neurological manifestations of AS, remain to be identified.
MKKS and the McKusick–Kaufman and Bardet–Biedl Syndromes
Authors: Biesecker Leslie G
Published: November 2023

McKusick–Kaufman syndrome (MKS) is a rare developmental anomaly syndrome originally described among the Amish that comprises polydactyly, hydrometrocolpos, and congenital heart disease (CHD) (Kaufman et al., 1972) (Fig. 132–1). Bardet–Biedl syndrome (BBS) is more common and manifests wider pleiotropy, comprising polydactyly, retinal degeneration, obesity, mental retardation, renal anomalies, and a wide array of other less common malformations (Beales et al., 1999). Both of these developmental anomaly syndromes can be caused by mutations in the MKKS gene (also known as BBS6) (Katsanis et al., 2000; Slavotinek et al., 2000; Stone et al., 2000) and are inherited in an autosomal recessive pattern, although rare families with BBS have evidence of more complex inheritance (Katsanis et al., 2001; Badano and Katsanis, 2002). BBS is genetically heterogeneous, and the MKS phenotype may be considered to be a mild form of BBS (see Chapter 155 for a complete discussion of BBS). The MKKS gene encodes a putative group II chaperonin similar to an archebacterial thermosome (Stone et al., 2000). Interestingly, another recently described BBS gene, BBS10, shows evidence of homology to the group II chaperonin family as well (Stoetzel et al., 2006). These data suggest that the pathogenesis of BBS and MKS are related to protein folding or misfolding.
PQBP1 and the Renpenning, Sutherland-Haan, Golabi-Ito-Hall, and Hamel Cerebropalatocardiac and XLMR Syndromes and Nonsyndromic XLMR
Authors: Schwartz Charles
Published: November 2023

The assumption was that proteins identified by the screen would be involved in the pathology of polyglutamine diseases. Indeed, subsequent studies clearly showed that PQBP1 interacts with ataxin-1 through its polar amino acid domain (Okazawa et al., 2002). This interaction apparently stimulates apoptosis leading to cell death. But the PQBP1 protein has another important role in developmental disorders beyond its involvement in polyglutamine diseases. Mutations in the gene result in numerous X-linked mental retardation (XLMR) syndromes: Renpenning (OMIM 309500, Renpenning et al., 1962; Stevenson et al., 1998), Golabi–Ito–Hall (Golabi et al., 1984), Sutherland–Haan (OMIM 309500, Sutherland et al., 1988), Hamel cerebropalatocardiac (OMIM 300463, Hamel et al., 1994), as well as MRX55 nonsyndromic XLMR (Deqaqi et al., 1998). That mutations in PQBP1 give rise to syndromic XLMR conditions is not surprising since it contains several important domains: a WW domain, which probably regulates gene expression by binding to RNA polymerase II (Komuro et al., 1999b; Okazawa et al., 2002; Llorian et al., 2004, 2005); a polar amino acid rich domain (PRD), which not only interacts with huntingtin (Busch et al., 2003) and ataxin 1 (Okazawa et al., 2002) but also inhibits the transcriptional activation of Brn2, a member of the family of POU domain containing transcription factors (Waragai et al., 1999); a nuclear localization signal (NLS) and a C-terminal domain (CTD) that binds to the small ribonucleoprotein, U5-15KD, which is a component of the U5 spliceosome complex (Reuter et al., 1999; Waragai et al., 2000; Okazawa et al., 2001).
TBCE and the Hypoparathyroidism–Retardation–Dysmorphism (HRD) Syndrome
Authors: Diaz George A , Parvari, Ruti , Hershkovitz Eli
Published: November 2023

Mutations in a tubulin-specific chaperone, TBCE, which encodes tubulin cofactor E, cause the syndrome of hypoparathyroidism, retardation, and dysmorphism [HRD; also known as Sanjad–Sakati or autosomal recessive Kenny–Caffey syndrome (KCS)]. Tubulin cofactors are essential for the biogenesis of native tubulin heterodimers, the basic unit of microtubules. On the basis of its established role in tubulin biogenesis, loss of TBCE function should be lethal, but mutation of the gene results instead in a pleiotropic disorder of growth failure, parathyroid gland aplasia, and neurological disease. In contrast, mutations in genes important for the regulation of microtubule growth primarily cause neurological diseases. The HRD disease phenotype is more global than predicted by the established role of the cofactor in tubulin biogenesis and highlights the existence of novel TBCE functions in the organization and regulation of the microtubule cytoskeleton.
LMNA and LBR and the Hutchinson–Gilford Progeria Syndrome and Associated Laminopathies
Authors: Gordon Leslie B , Brown, W Ted , Rothman Frank G
Published: November 2023

Hutchinson–Gilford Progeria Syndrome (HGPS), also referred to as childhood progeria, is an extremely rare, uniformly fatal, segmental “premature aging” disease in which children exhibit some phenotypes of aging in their early years. All children die as a consequence of severe atherosclerosis at an average age of 13 years (range 8–21 years) (DeBusk, 1972; Hennekam, 2006). There is no known treatment or cure. Until recently, no progress was made on the genetics of this disease. Then, in 2003, the genetic basis for HGPS was uncovered (Cao and Hegele, 2003; De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003), and HGPS joined a family of genetic dis- eases known as the laminopathies, whose causal mutations lie along the LMNA gene (Capell and Collins, 2006; Mattout et al., 2006; Rankin and Ellard, 2006). Lamin proteins produced by this gene act as key structural and cell signaling elements of the inner nuclear membrane of most differentiated cells (reviewed in Gruenbaum et al., 2003).
An Introduction to Guanine Nucleotide–Binding Proteins
Authors: Newey Sarah E , Aelst Linda Van
Published: November 2023

Guanine nucleotide–binding proteins (GNBPs) regulate a vast array of physiological processes from cell growth and differentiation to sensory perception. There are two major families. First, the small, monomeric GTPases, whose founder member, Ras, is known to be important in regulating cell growth. Second, the heterotrimeric G proteins that are coupled to G protein–coupled receptors (GPCRs), through which many physiological and developmental processes are regulated. These families of proteins act as molecular switches, cycling between an inactive guanosine diphosphate (GDP) bound state and an active guanosine triphosphate (GTP) bound state, transducing extracellular signals to downstream signaling components. Here we give an introduction to the monomeric and heterotrimeric protein superfamilies and consider how these proteins are regulated, the signaling pathways in which they participate, and, ultimately, how these signals from multiple family members are integrated to generate a biological response.
Microtubule Motors: Intracellular Transport, Cell Division, Ciliary Movement, and Nuclear Migration
Authors: Youn Yong-Ha , Pramparo, Tiziano , Wynshaw-Boris Anthony
Published: November 2023

Intracellular motility in eukaryotic cells is generated by motor proteins, which drive directional transport along cytoskeletal filaments such as microtubules, the primary intracellular rail system. These cytoplasmic cytoskeletal elements provide not only structure and support to the cell but also an intracellular directional railway that allows components of the cell to be transported outside of organelles (Hirokawa and Takemura, 2005). This railway system transports molecular complexes and organelles after synthesis in the cell body to their proper peripheral location. Similarly, endocytic vesicles are transported from the cell surface to the center of the cell. In the cell, microtubule plus ends are directed toward the cell membrane and minus ends are anchored at the centrosome, one type of the microtubule-organizing center (MTOC) in a cell.
Lissencephaly with Cerebellar Hypoplasia
Authors: Olson Eric C , Walsh Christopher A
Published: November 2023

Lissencephaly with cerebellar hypoplasia (LCH) is characterized by abnormal development of both the cerebral cortex and cerebellum. LCH is distinguished from classical lissencephaly (Chapter 150) by profound cerebellar hypoplasia and less severe cortical malformations. The cortical malformation in LCH is described by the term “pachygria”, (thick gyri), a term that contrasts with agyria found in severe forms of lissencephaly. LCH is inherited in an autosomal recessive fashion, and is associated with profound neurological disability, including ataxia, hypotonia, mental retardation and seizures. One form of LCH is associated with mutations in the Reelin gene (RELN), the human ortholog of the murine Reln gene, which was originally discovered as mutated in the mutant reeler mouse. Using the reeler mouse model, a great deal of progress has been made in understanding the signaling mechanisms triggered by Reelin, and other members of the Reelin signaling pathway are candidate genes for additional forms of human LCH.
The Bardet–Biedl Syndromes
Authors: Sheffield Val C , Zhang Qihong , Heon Elise , Stone, Edwin M , Carmi Rivka
Published: November 2023

BARDET–BIEDL SYNDROME

Bardet–Biedl syndrome (BBS) (OMIM 209900) is a heterogeneous autosomal recessive disorder characterized by a combination of clinical findings that include obesity, photoreceptor degeneration, polydactyly, hypogenitalism, renal abnormalities, and developmental delay (Ammann, 1970; Alton and McDonald, 1973; Harnett et al., 1988; Green et al., 1989). Clinical characterization and the nomenclature describing this syndrome have evolved over time. In 1866, Laurence and Moon reported a syndrome consisting of mental retardation, retinal degeneration, hypogonadism, ataxia, and spas- tic paraplegia. Nearly six decades later, Bardet (1920) and Biedl (1922) independently described patients with the additional clinical features of polydactyly and obesity (Bardet, 1920; Biedl, 1922). Subsequently, Solis-Cohen and Weiss (1924) reported a single fam- ily that had features that overlapped those described by Laurence and Moon (1866), Bardet (1920), and Biedl (1922), suggesting the name Laurence–Moon–Biedl syndrome (Bardet, 1920; Biedl, 1922; Solis-Cohen, 1924). The disorder was later referred to in the scienti2c and medical literature as Laurence–Moon–-Bardet–Biedl syndrome (McLoughlin and Shanklin, 1967; Klein and Ammann, 1969). The Laurence–Moon–Bardet–Biedl syndrome has in general been viewed as two distinct clinical disorders. BBS is used to refer to patients and families that have the minimum findings of retinopathy, obesity, and polydactyly without spastic paraplegia. Patients affected with Laurence–Moon syndrome do not have polydactyly (Ammann, 1970). Although BBS is considered to be rare, it is the more common of the two syndromes. The incidence in the general population is often cited as being less than 1:100,000 (Klein and Ammann, 1969; Lofterod et al., 1990; Croft et al., 1995; Beales et al., 1997).
SNAP29 and Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Palmoplantar Keratoderma syndrome
Authors: Mandel Hannah , Sprecher Eli , Rapaport, Debora , Horowitz Mia
Published: November 2023

Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma (CEDNIK) is an autosomal recessive neurocutaneous syndrome recently described in Northern Israel and resulting from aberrant function of SNAP29, a protein involved in the regulation of vesicle trafficking.