bluuebunny/crossref_metadata_2025 huggingface dataset:
Consequences of the Genome Project for Understanding Development
Authors: Peltonen Leena
Published: November 2023

Our possibilities to characterize the details of development have been transformed by the detailed characterization of the genome landscape of humans and other species. The development of “global” technologies, producing information of alleles and transcript levels of all the genes in one single experiment, has provided us with unprecedented possibilities in identifying molecules and pathways driving development. For improved understanding of human development, the exponentially increasing wealth of information of the genome structure and function of other species has proven extremely important. Numerous details of genes and molecular networks critical for normal development have emerged from experimental studies on species such as nematode and Drosophila, whose genome sequence was established earlier than humans, and on zebra7sh that due to ex utero development of the embryos represents in many ways an ideal system for studying vertebrate embryogenesis. Systematic interruption of individual genes in these model organisms, either using targeted insertion of a transposomal element or targeted interruption of speci7c genes based on the homologous recombination and subsequent detailed monitoring of produced phenotypes, has taken place and the data is exposed on the Web. The parallel process is on-going for the mouse genome; the predicted time table for the completion of the project with all approximately 20,000 mouse genes being individually knocked out is 2009. These resources, including commonly accessible experimental tools such as My strains or mouse embryonic stem (ES) cell lines each carrying a targeted mutant have transformed biological modeling of developmental aberrations and guided our thinking of critical developmental pathways. This wealth of experimental possibilities has resulted in an immense amount of novel information stored in databases. Such massive datasets cannot be properly analyzed without novel statistical and bioinformatics-based analyses. The system biology–based strategies, combining large experimental datasets and advanced biocomputational analyses, are needed to establish a comprehensive view into genes and pathways critical for development.
Development of the Eye
Authors: Rainger Joe , Heyningen, veronica Van , patrick david r. Fitz
Published: November 2023

The development of the vertebrate eye is a remarkable process involving complex morphogenesis and tissue interactions. Although a reasonable body of descriptive data is available for the early developmental anatomy of the human eye, there is a paucity of in situ molecular information as a result of appropriate ethical constraints and the scarcity of relevant biological material. Inevitably much of our knowledge of the mechanisms involved in ocular development comes from animal models. Most aspects of morphogenesis and speci7c molecular mechanisms appear to be conserved among vertebrates. Amphibian (Xenopus laevis), 7sh (Danio rerio and Oryzias latipes), avian (Gallus gallus), and mammalian (Mus musculus) systems have been utilized.
Mira Irons
Authors: Iannaccone Philip
Published: November 2023

The importance of cholesterol metabolism in humans has been recognized for decades. Cholesterol is a major structural component of cell membranes and of myelin. It is also a precursor of bile acids and steroid hormones, including sex steroids, glucocorticoids, mineralocorticoids, neurosteroids, and oxysteroids. While the role of cholesterol in these important biochemical processes has been known for some time, the essential role of cholesterol and the cholesterol metabolic pathway in human development has only been more recently appreciated with the identification of inborn errors of cholesterol metabolism that result in human phenotypes that include structural malformations, as well as growth and mental retardation.
ZIC3, CFC1, ACVR2B, and LEFTY2 and the Visceral Heterotaxies
Authors: Ware Stephanie M , Belmont John W
Published: November 2023

Heterotaxy is a clinical phenotype resulting from a failure to correctly establish left/right (L/R) patterning during embryogenesis. Multiple congenital anomalies may result from discordant positioning of normally asymmetrical internal organs and vasculature. Midline defects and anomalies of paired organs can occur, presumably owing to a failure to correctly segregate left and right. Mutations in three genes that function in the transforming growth factor-β (TGF-β) signaling pathway, Activin receptor type IIB (ACVR2B), the epidermal growth factor-cripto/FRL1/cryptic (EGF-CFC) family member CRYPTIC, and LEFTY2 (LEFTYA, EBAF), have been found in a small number of patients with heterotaxy. Mutations in the zinc finger transcription factor ZIC3 have been described in familial and sporadic cases of heterotaxy, as well as in cases of isolated congenital heart disease (CHD). The degree to which genes involved in L/R patterning may contribute to isolated congenital anomalies as opposed to classic heterotaxy is not currently known, and the incidence of these genetic defects may be underappreciated. A molecular understanding of the important events in the generation of L/R patterning, including TGF-β signaling in the node and left lateral plate mesoderm (LPM) of the gastrulation-stage embryo, is emerging. Studies in mouse, chick, Xenopus, and zebrafish are contributing to the delineation of the developmental pathogenesis of these disorders, as well as identifying candidate genes for further investigation.
EDA, EDAR, and EDARADD and the Hypohidrotic Ectodermal Dysplasias and the Ectodysplasin Signaling Pathway
Authors: Zonana Jonathan
Published: November 2023

The ectodermal dysplasia syndromes are a group of heterogeneous inherited disorders that display different combinations of congenital defects of the hair, teeth, nails, and sweat glands (Pinheiro and Freire-Maia, 1994). These structures are all appendages derived from oral and epidermal ectoderm, and are formed during development by reciprocal molecular interactions between the epithelium and the mesenchyme (see Chapter 18) (Fuchs and Raghavan, 2002; Courtney et al., 2005; Mou et al., 2006). The pathology seen in these conditions ranges from aplasia or hypoplasia to dysplasia of the affected structures. The defects are secondary to the abnormal induction, proliferation, or differentiation of the epidermal appendages during morphogenesis. The hypohidrotic, or anhidrotic, ectodermal dysplasias (HED or EDA) are a subgroup of the ectodermal dysplasias that have in common significant abnormalities of the eccrine sweat glands, resulting in diminished or lack of sweating (hypohidrosis or anhidrosis) and abnormalities of teeth and hair (Table 42–1). Positional cloning studies in both humans and mice have revealed that the genetic loci responsible for these disorders form a previously unknown developmental pathway. The protein products of each of these loci are expressed in the epithelial cells of the developing teeth, hair follicles, and eccrine sweat glands during embryonic development, and loss of their function results in abnormal morphogenesis.
FGF10, FGFR2, and FGFR3 and the Lacrimo-Auriculo-Dental-Digital (LADD) Syndrome
Authors: Milunsky Jeff M
Published: November 2023

Lacrimo-Auriculo-Dento-Digital [LADD (MIM 149370)] syndrome is an autosomal dominant multiple congenital anomaly disorder characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies. This disorder is also known as the Levy–Hollister syndrome from the original descriptions (Levy, 1967; Hollister et al., 1973). Aplasia or hypoplasia of the lacrimal and salivary glands [ALSG (MIM 180920; MIM 103420)] is also a rare autosomal dominant disorder characterized by xerophthalmia and xerostomia, which lead to conjunctival scarring, severe dental caries, dental erosion, and periodontal disease. LADD syndrome and ALSG appear to represent variable presentations of the same clinical spectrum caused by FGF10 mutations. In addition to FGF10 mutations, LADD syndrome is a genetically heterogeneous disorder with identified mutations in FGFR2 and FGFR3, the genes for binding receptors of FGF10. Hence, LADD syndrome results from the mutations affecting the FGF10 signaling pathway.
JAG1 and NOTCH2 and the Alagille Syndrome
Authors: Spinner Nancy B , Krantz Ian D
Published: November 2023

Alagille syndrome (AGS), also known as syndromic bile duct paucity or arteriohepatic dysplasia, is a multisystem, autosomal dominant, developmental disorder. Alagille et al. >rst reported this syndrome in 1969 with emphasis on the hepatic manifestations. Subsequently, Watson and Miller in 1973 focusing more on the cardiac >ndings described the same entity. In 1975, Alagille et al. formally described the syndrome, which carries his name, and speci>c diagnostic criteria were established. AGS is the most common form of familial cholestatic liver disease. In addition to the liver, AGS is characterized by abnormalities of the heart, eye, and skeleton and a characteristic facial appearance. Renal and neurovascular abnormalities are also common (Alagille et al., 1987; Emerick et al., 1999; Lykaveris et al., 2003; Kamath et al., 2004). The prevalence of AGS has been reported as 1 in 70,000 live births, although this is most likely an underestimate as these patients were ascertained solely on the basis of the >nding of neonatal liver disease (Danks et al., 1977). It was recently demonstrated that only 31% of individuals with a disease-causing mutation have cholestasis, so a revised estimate of the prevalence is closer to 1/20,000 (Kamath et al., 2003). AGS is characterized by highly variable expressivity (Watson and Miller, 1973; Alagille et al., 1987; Krantz et al., 1999; Kamath et al., 2003), and the wide range of phenotypic presentations has been better appreciated since the identication of the disease-causing genes.
DLL3, MESP2, and LFNG and Spondylocostal Dysostosis
Authors: Turnpenny Peter D , Kusumi, Kenro , Dunwoodie Sally
Published: November 2023

Spondylocostal dysostosis (SCD) is a short trunk, short stature condition due to multiple vertebral segmentation defects (MVSDs), usually accompanied by rib fusions. A mild, nonprogressive kyphoscoliosis is present, usually without additional abnormalities. Three notch signaling pathway genes are now linked to autosomal recessive (AR) SCD: the delta-like 3 (DLL3) gene (SCD1), which maps to chromosome 19q13.1 in man, encodes a ligand for the Notch family of receptors, shows spatially restricted patterns of expression during somite formation, and has a signi>cant developmental role in somitogenesis and in patterning events of sclerotomal tissues; the mesoderm posterior 2 (MESP2) gene (SCD2), which maps to 15q26, is a basic helix–loop– helix (bHLH) transcription factor expressed in the anterior presomitic mesoderm; and lunatic fringe (LNFG), a cycling, or oscillator gene (SCD3) that maps to chromosome 7p22. DLL3 is the most commonly implicated gene causing monogenic AR SCD and the phenotype is characterized by consistent radiological features. In childhood, the vertebral bodies have smooth outlines for which we coined the term “ ‘pebble beach’ sign.” SCD2, due to mutated MESP2, is rare and the vertebral bodies are more angular in appearance. SCD3, due to mutated LNFG, is also rare and is characterized by more severe truncal shortening because of marked segmentation abnormalities, particularly of the thoracic vertebrae. SCD is distinct from the very severe truncal shortening condition that appears to be relatively common in Puerto Rico spondylothoracic dysplasia (STD), also demonstrating AR inheritance, in which the ribs fan out with a crab-like appearance on X-ray. Abnormal vertebral segmentation is a common developmental defect and the radiological phenotypes are very diverse; cases demonstrating clear Mendelian inheritance are relatively rare.
TSC1 and TSC2 and Tuberous Sclerosis
Authors: Kwiatkowski David J
Published: November 2023

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas and hamartias in several organ systems. It is due to inactivating mutations in either the TSC1 gene or the TSC2 gene. With the possible exception of cortical tubers, TSC lesions follow the >rst germline hit–second somatic hit tumor suppressor gene paradigm. The TSC1 and TSC2 proteins form a complex, which functions as a GTPase Activating Protein (GAP) for the ras homologue enriched in brain (rheb) GTPase, which has an important role in the regulation of the activity of the mammalian target of rapamycin (mTOR) kinase. Clinically, TSC is characterized by the involvement of brain with the hallmark cortical tubers as well as subependymal lesions, several types of cutaneous lesions, renal angiomyolipomas (AMLs), cardiac rhabdomyomas, and pulmonary lymphangioleiomyomatosis (LAM). There is a high sporadic case rate, and both genes have a wide spectrum of mutations though mutations in TSC2 are seen four times more commonly than in TSC1. TSC2 disease is signi>cantly more severe than TSC1 disease. Clinical management focuses on seizure control, neurodevelopmental assessment and educational assistance, and monitoring of brain and kidney for lesion
NSD1 and Sotos Syndrome
Authors: Visser Remco , Matsumoto Naomichi
Published: November 2023

Sotos syndrome (OMIM 117550) is a childhood overgrowth syndrome characterized by accelerated growth, typical craniofacial features, and a certain level of learning impairment. Sotos syndrome is caused by haploinsufficiency of the Nuclear receptor binding SET Domain protein 1 (NSD1) gene at 5q35.2-q35.3. Genetic analysis has established insight in the spectrum of genomic abnormalities of NSD1, in the underlying mechanisms of NSD1 microdeletions and in the genotype– phenotype correlation in Sotos syndrome. However, the functional roles of NSD1 are yet largely unknown. A major role of NSD1 seems to lie in the transcriptional regulation of chromatin through the histone methyltransferase activity of its Su(var) 3–9, Enhancer of zeste, Trithorax (SET) domain. Furthermore, the nuclear receptor interacting domains (NIDs) are thought to be involved in transcriptional regulation by acting as both a coactivator and corepressor of nuclear receptors. Identification of interacting proteins and mapping of NSD1 into causative signaling pathways are the challenging future tasks in Sotos syndrome in order to clarify the link between genetic abnormalities and the Sotos phenotypic characteristics.
TFAP2B and the Char Syndrome
Authors: Veetil Sindhu , Gelb Bruce D
Published: November 2023

Char syndrome, a disorder affecting cardiovascular, craniofacial, and limb development, results from altered activity of the transcription factor, TFAP2B. Mutant TFAP2B alleles act in a dominant-negative or haploinsufficient fashion. Homoand heterodimers containing mutant TFAP2B molecules either do not bind target gene sequences or fail to transactivate gene expression properly.
RAI1 and the Smith–Magenis and Potocki–Lupski Syndromes
Authors: BI WEIMIN , LUPSKI JAMES R
Published: November 2023

Smith–Magenis syndrome (SMS; MIM 182290) is a multiple congenital anomalies/mental retardation disorder with characteristic craniofacial and neurobehavioral features including sleep disturbance, self-injurious behaviors, and stereotypical behaviors. Most SMS patients have an approximately 3.7 Mb hemizygous interstitial deletion of chromosome 17p11.2, which is caused by nonallelic homologous recombination (NAHR) between two 0anking low-copy repeats (LCRs) termed SMS-REPs. The reciprocal recombination results in duplication of the 17p11.2 region and the newly de7ned Potocki– Lupski syndrome (PTLS; MIM 610883), a neurological disease with features of autism. Mutations in the retinoic acid (RA) induced 1 gene (RAI1; MIM 607642) have been identi7ed in phenotypic SMS patients without 0uorescence in situ hybridization (FISH) detectable deletions. Haploinsuf7ciency of RAI1 causes the majority of the SMS characteristics as determined by both human and mouse studies; whether or not PTLS results from RAI1 gene dosage remains to be elucidated.
FMR1 and the Fragile X Syndrome
Authors: Garber Kathryn B , Gruskin, Daniel , Warren Stephen T
Published: November 2023

Fragile X syndrome (FXS) is an X-linked dominant disorder with reduced penetrance whose primary manifestation is moderate-to- severe mental retardation. It is most often caused by the transcriptional silencing of the FMR1 gene due to an expansion of a CGG-repeat found in the 5’ untranslated region (UTR). This allelic class, with greater than 200 CGG-repeats, is referred to as the full mutation. Normal alleles have up to 54 repeats with the 30 repeats being most common. Intermediate between normal and full mutation alleles are the premutation alleles with 55–200 repeats. Premutation alleles are unstable upon meiotic transmission and the size of the maternal premutation is directly correlated with the risk of having a full mutation offspring. Besides the genetic risk of FXS, premutation alleles may also lead to premature ovarian failure (POF) in females or a neurodegenerative disorder, most often in elderly males. Full mutation alleles lead to the lack of the fragile X mental retardation protein, FMRP, due to the transcriptional silencing of FMR1. FMRP is a selective RNA-binding protein that is a negative regulator of local protein synthesis in neuronal dendrites. FMRP appears to function in relation to the positive translational stimulation caused by group 1 metabotropic glutamate receptor (mGluR) activation. In the absence of FMRP, the transcripts normally regulated by FMRP are overtranslated.
VHL and von Hippel–Lindau Disease
Authors: Maher Eamonn R
Published: November 2023

Von Hippel–Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by germline mutations in the 3p25 VHL tumor-suppressor gene (Latif et al., 1993; Kaelin and Maher, 1998; Maher 2004; Haase, 2005; Kaelin, 2005 ). VHL is widely expressed in fetal and adult tissues, and the pattern of VHL mRNA expression in the fetal kidney is consistent with a role in normal renal tubular development and differentiation (Richards et al., 1996). Mouse models of VHL disease have demonstrated that VHL expression is critical for normal extraembryonic vascular development such that homozygous Vhlh−/− mice died in utero at 10.5–12.5 days of gestation and conditional mouse knockout models have demonstrated renal cysts but not tumors whereas in other tissues, inactivation of pVHL resulted in abnormal differentiation associated with decreased cell proliferation, suggesting tissue-specific effects of Vhlh (Haase et al., 2005). Reintroduction of pVHL into VHL null renal cell carcinoma (RCC) cells suppresses tumor formation consistent with a classical tumor suppressor gene, but complex genotype–phenotype correlations in VHL disease suggest that pVHL has multiple, and tissue-specific functions. The best-studied function of pVHL is its role as a component of an E2 ubiquitin ligase complex that regulates expression of the HIF (hypoxia inducible factor) transcription factors such that loss of pVHL is associated with HIF-induced activation of hypoxia response genes. In addition, pVHL has been implicated in normal developmental apoptosis of sympathetic neuronal precursor cells (Lee et al., 2005).
Dermato-Ungual-Lacrimal-Digit (ADULT), and Rapp–Hodgkin Syndromes and Ectrodactyly (Split Hand/Foot Malformation)
Authors: Bamshad Michael J
Published: November 2023

P63 is a homologue of the prototypic tumor suppressor gene, TP53. Mutations in TP63 are found in 90% of individuals who have one of five different multiple malformation syndromes: (1) ectodermal dysplasia, ectrodactyly, and cleft lip and/or palate (EEC) syndrome (OMIM 604292); (2) limb–mammary syndrome (LMS) (OMIM 603543); (3) ankyloblepharon, ectrodactyly, and cleft lip/palate (AEC) syndrome (or Hay–Wells syndrome) (OMIM 106260); (4) acro-dermato-unguallacrimal-tooth (ADULT) syndrome (OMIM 103285); and (5) Rapp– Hodgkin syndrome (OMIM 129400). All of these syndromes are characterized by ectodermal defects accompanied by limb malformations that range from subtle to severe. A small percentage of patients with isolated ectrodactyly [split-hand/foot malformation (SHFM)] syndrome (OMIM 605289) also have mutations in TP63. All of these conditions can usually be distinguished from each other and from rarer disorders through the use of clinical criteria, although mutation analysis can be helpful, particularly in sporadic cases. The long-term care of patients with syndromes caused by mutations in TP63 can be challenging, but, in general, most patients do well. None of these conditions is associated with an increased predisposition to tumor suppression, although p63 clearly plays role in tumor suppression in the general population (Moll and Slade, 2004; Koster et al., 2006; Mills, 2006; Rocco and Ellisen, 2006). TP63 is widely expressed in the progenitor epithelial cells of many different tissues and organs; this includes the region of specialized ectoderm covering the developing limb that in part controls outgrowth of the limb bud. Trp63−/− deficient mice have malformations of the epidermis and its appendages, severe truncation defects of the limbs, and craniofacial abnormalities, fully recapitulating EEC syndrome. Individuals heterozygous for deletions of TP63 do not have EEC syndrome. This is consistent with in vitro studies of mutant p63 proteins, which suggest that development is disrupted by either gain-of-function or dominant-negative effect. As a consequence, commitment of ectoderm to an epithelial lineage and terminal differentiation of epithelial cells is impaired.
RAB3GAP1 and RAB3GAP2 and the Warburg Micro and Martsolf Syndromes
Authors: Aligianis Irene , Maher Eamonn R
Published: November 2023

Warburg Micro syndrome (OMIM 60018) and Martsolf syndrome (OMIM 21270) are autosomal recessive neurodevelopmental disorders that may result from the dysregulation of the Rab3 pathway. Inactivating germline mutations in RAB3GAP1, which encodes the catalytic subunit of the heterodimeric Rab3 GTPase-activating pro- tein (Rab3GAP), cause Micro syndrome in approximately 60–70% of cases. Mutations in the noncatalytic subunit, RAB3GAP2, have been associated with Martsolf syndrome. Micro syndrome is a severe disorder characterized by ocular (microphthalmos, microcornea, congenital cataracts, optic atrophy); neurodevelopmental (microcephaly, cortical gyral abnormalities—polymicrogyria, hypoplasia of the cor- pus callosum, severe learning disability, spastic cerebral palsy) and endocrine abnormalities. Martsolf syndrome has an overlapping but less severe phenotype. In both disorders, there is also evidence for locus heterogeneity.
DNAH5 and Primary Ciliary Dyskinesia (Kartagener Syndrome)
Authors: Witt Michal
Published: November 2023

Primary ciliary dyskinesia (PCD), formerly known as immotile cilia syndrome (ICS) belongs to a group of human genetic disorders caused by dysfunctions of organelles, analogous to mitochondrial, lysosomal, or peroxisomal disease. PCD is a human disorder caused by a primary dysfunction of the ciliary apparatus. In 1933, the Swiss physician Manes Kartagener described four cases of coexisting situs inversus, bronchiectasis, and chronic sinusitis (Kartagener, 1933). Later this set of symptoms was named the Kartagener triad, or Kartagener syndrome (KS). In fact, a Russian author, Siewert, was first to describe a case of the disease in 1904, but it was Kartagener who suggested the common pathomechanism of all three symptoms described. In the 1970s, it was found that the sperm and respiratory cilia of males with KS are immotile due to the defect of a ciliary kinetic apparatus observed on the utrastructural level in the electron microscope and that this causes both chronic bronchopulmonary diseases and male infertility (Afzelius, 1976; Elliason et al., 1977). Afzelius (1976) coined the term “immotile cilia syndrome,” which has been gradually replaced by “dysmotile cilia syndrome” and 2nally by “PCD.”
FLNA and FLNB and Periventricular Nodular Heterotopia, the Otopalatodigital Spectrum Disorders, Spondylocarpotarsal Synostosis, Larsen Syndrome, and Atelosteogenesis Types I F and III
Authors: Robertson Stephen P , Krakow Deborah
Published: November 2023

Filamins A, B, and C are cytoskeletal proteins that act by cross- linking the actin cytoskeleton into an orthogonal architecture. Structurally, 2lamin proteins are composed of an N-terminal actinbinding domain and an array of 24 structurally homologous, immunoglobulin-like domains that bind a broad diversity of transmembrane and juxtamembrane proteins. These interacting proteins mediate multiple signaling events as well as regulate secretion and interactions with the extracellular matrix. Loss-of-function mutations in FLNA and FLNB lead to a neuronal migration disorder, X-linked dominant periventricular nodular heterotopia (PH), and a skeletal dysplasia, autosomal recessive spondylocarpotarsal syndrome (SCT), respectively. PH is clinically characterized principally by epilepsy, while SCT presents with short stature and vertebral, carpal, and tarsal fusions. In sharp contrast to these disorders, clustered missense mutations predicted to introduce substitutions or small in-frame deletions and insertions into FLNA and FLNB produce markedly different phenotypes. Mutations that preserve the translational reading frame in FLNA lead to a group of skeletal dysplasias termed the otopalatodigital syndrome spectrum disorders (OPSDs). The phenotypic severity of these conditions is very broad. In otopalatodigital syndrome type 1 (OPD1), the mildest OPSD, affected males have hearing loss, cleft palate, and mild digital anomalies. Male offspring of females manifesting Melnick–Needles syndrome (MNS), the most severe condition, typically die in midgestation. A similar range of clustered mutations in FLNB lead to a group of conditions characterized by a skeletal dysplasia, joint dislocations, and craniofacial anomalies—the Larsen-atelosteogenesis (LS-AO) spectrum. Again, the range of phenotypes is broad—from large joint dis- locations in Larsen syndrome (LS) to perinatal lethal atelosteogenesis type I (AOI) in which skeletogenesis is grossly disordered.
VPS33B and the Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome
Authors: Gissen Paul , Maher Eamonn R
Published: November 2023

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (OMIM 208085) is a severe multisystem autosomal recessive disorder 2rst described in the 1970s, and to date, approximately 50 cases of ARC have been reported (see Gissen et al., 2006 and references within). Although the variability in liver biopsy 2ndings initially suggested possible genetic heterogeneity, Horslen et al., 1994 coined the eponym of ARC syndrome and reported that although the hepatic changes may show intrafamilial variability, the other features were usually consistent. Subsequently a high prevalence of ichthyosis, abnormal platelet morphology, intracranial defects, and diarrhea was noted. Many reported families were consanguineous, consistent with autosomal recessive inheritance. Although the hepatic features of ARC and progressive familial intrahepatic cholestasis (PFIC) overlap, linkages to PFIC-1 and PFIC-2 loci were excluded, and the locus for ARC syndrome was mapped to chromosome 15q26.1 using autozygosity mapping approach and germline mutations were identi2ed in VPS33B (Gissen et al., 2004). VPS33B is a homologue of yeast vps33 gene involved in vacuolar biogenesis and in vesicular traf2cking at different stages of the endocytosis and exocytosis (Gallwitz et al., 2003). Yeast vps33 encodes a class C vacuolar protein sorting (vps) protein whose inactivation results in severe cellular defects including temperature-sensitive growth restriction, abnormalities in the amino acid pool, and vacuolar biogenesis defects. VPS33B contains a Sec1- like domain and belongs to the family of SM (Sec1/Munc18) proteins that bind tightly to members of the syntaxin family of target-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors or SNAP receptor proteins). SM proteins can exert inMuence upon the SNARE-complex formation and may provide speci2city to the vesicular fusion events.
SEC23A and Cranio-Lenticulo-Sutural Dysplasia
Authors: Boyadjiev Simeon A
Published: November 2023

Approximately one-third of all cellular proteins are synthesized in association with the endoplasmic reticulum (ER). The coat protein complex II (COPII) transport vesicles represent the first step of the intracellular secretory pathway responsible for the traffic of secretory, plasma membrane and vacuolar proteins from the ER to the ER-Golgi intermediate compartment (ERGIC) and ultimately to the cis-Golgi complex (Schekman and Orci, 1996; Duden, 2003). The combination of cytoplasmic coat proteins determines the characteristics of the COPII- and COPI-coated vesicular carriers that mediate the anterograde and retrograde ER-to-Golgi transport, respectively. In addition to determining the directionality of the vesicular secretory pathway, the combination of coat proteins determines the specificity of the cargo and targeting SNARE proteins to be transported. For additional details, please see Supplementary section Secretory pathway and SEC23A locus overview.
COMP and Pseudoachondroplasia
Authors: Rock Matthew J , Cohn Daniel H
Published: November 2023

Pseudoachondroplasia (PSACH) is a dominantly inherited form of short-limb short stature. Both mild and typical forms are recognized, comprising a spectrum of clinical severity. A definitive diagnosis can be made on the basis of radiographs showing delayed epiphyseal ossification, epiphyseal and metaphyseal irregularities, and a characteristic anterior beaking of the vertebral bodies apparent on lateral projection. In addition to short stature, loose joints due to ligamentous laxity, joint pain, varus and/or valgus deformities at the knees and scoliosis characterize the phenotype. The major complication is degenerative joint disease, particularly in the hips, which can lead to joint replacement in the third or fourth decade of life. Patients with PSACH have defects in cartilage oligomeric matrix protein (COMP), a pentameric glycoprotein of the extracellular matrix. Most patients with typical PSACH studied to date have been shown to be heterozygous for structural mutations in the COMP gene, either missense mutations or small deletions. The phenotype appears to primarily result from reduced secretion of COMP, the presence of abnormal COMP in the extracellular matrix, and disrupted interactions between COMP and other matrix molecules.
KRIT1, Malcavernin (CCM2), and PDCD10 in the Pathogenesis of Cerebral Cavernous Malformations
Authors: Akers, Amy L , Marchuk Douglas A
Published: November 2023

Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system consisting of closely packed, grossly enlarged capillary-like vessels. The lesions range in size from a few millimeters to several centimeters and are defined by surrounding connective tissue, but remain distinct from neural parenchyma. Incidence in the general population is 0.1%–0.5% (Rigamonti et al., 1988). Individuals affected with CCM often present in the third to fifth decades of life with symptoms of recurrent headaches, focal neurological defects, seizures, and intracerebral hemorrhage. Intracerebral hemorrhage of the CCM lesion often leads to stroke. In many cases, this fatal event is the first and only clinical presentation of the disorder (Maraire and Awad, 1995).
Müller’s Net
Authors: Lab Mullers
Published: November 2023

Johannes Müller was born in Koblenz on 14 July 1801, and his life reflects the shifts of nineteenth-century politics as a seismograph records the earth’s motions. Since his untimely death in 1858, students and historians have been turning his life into contrasting stories. Müller’s father was a cobbler who wanted his son to become a saddle maker, but even these simple facts, formulated in different ways, have become the starting points for contradicting tales. In his memorial address for Müller, Emil du Bois-Reymond called Müller’s father “a shoemaker in good circumstances, “ whereas the more liberal Rudolf Virchow described Müller as “the shoemaker’s son. “1 In his history of the Berlin University, Max Lenz represented Müller senior as “an honorable master shoemaker. “2 In the late twentieth century, the medical historian Johannes Steudel called Müller’s father “a reputable master craftsman, the owner of a large leather-working shop, “ whereas the historian of science Nelly Tsouyopoulos depicted Müller as a “son of the working class [Handwerkerklasse]. “3 According to preference, even this basic information from Müller’s students has permitted the creation of a different father, either a well-to-do artisan or a humble cobbler. Putting the students’ statements into their own words, historians have told the stories they wanted to tell. Müller’s social origin is highly significant, since his fear of poverty and respect for his Prussian mentors would give him a conservative outlook inimical to some of his students. But historians have represented it varyingly, and it is not easily defined in modern terms. Müller’s father worked with his hands but earned enough to send his son to the Koblenz Gymnasium, an elite high school designed to prepare students for university study.
Emil du Bois-Reymond as a Scientific and Literary Creator
Authors: Lab Mullers
Published: November 2023

Emil du Bois-Reymond, who worked with Müller from 1840 until 1858, wrote the official story of his mentor’s life. When Müller died in April 1858, the Academy of Sciences asked him to deliver a memorial address, and he spent over a year revising his talk into a substantial biography. In this account, du Bois-Reymond depicted Müller’s work so as to promote his own scientific views.1 Like Schwann, he believed that physical laws could explain life functions, which should be investigated through rigorous quantitative experiments. Consequently, du BoisReymond portrayed Müller as a scientist who inspired experimental physiology but failed to practice it himself (at least, after 1840), losing himself in useless speculation about how life force realized itself in a grand plan. For du Bois-Reymond, science meant action: creative, innovative adaptations of technology to investigate physiological phenomena.
Rudolf Virchow’s Scientific Politics
Authors: Lab Mullers
Published: November 2023

Rudolf Virchow differs from all of Müller’s other students discussed in this book in that he studied medicine because he wanted to practice it. For the others, a medical degree offered a way to learn science, but clinical practice was an undesirable fallback. Although Virchow became as renowned a scientist as any of the others, he grounded his work in practical medicine. His clinical outlook affected his experiences with Müller and the way that he represented his teacher for posterity.
Developmental and Hereditary Optic Nerve Disorders
Authors: Kline Lanning B , Eng, Eugene H , Siatkowski R Michael
Published: November 2023

Although a large body of literature deals with developmental anomalies of the optic nerve, the ophthalmologist encounters only a few in routine clinical practice. This chapter discusses these developmental disorders and the more common forms of hereditary optic nerve disease. At times, optic disc anomalies may mimic an acquired optic neuropathy. Prompt recognition of developmental and hereditary disorders of the optic nerve eliminates unnecessary patient evaluation.
The End of Prescribing; Why Prescription Writing Is Irrational
Authors: Veatch Robert M
Published: November 2023

In chapter 9 we discussed the foolishness of the note from the doctor. Yet, doctors write notes for their patients constantly. The law requires it for patients who want to get any of thousands of drugs. These drugs sometimes are called “legend”; drugs. Even more outrageously, some manufacturers call them “ethical”; drugs. The form the doctor signs is called a prescription.1 It is a note to a pharmacist that is actually a legal document, an authorization for the pharmacist to dispense to the patient a drug that is otherwise, by federal law, illegal to possess. How did we get ourselves in the absurd position that mature adults in a free country cannot possess beneficial drugs for their own use unless they can find some physician someplace who will write them a note? The physician who writes the note need not know the patient. He or she need not even have met the patient. He can prescribe over the telephone. In order to decide that the person desiring the medication is worthy of it, logic tells us that the physician ought to determine that the drug is good for the patient—that it is reasonably likely to do more good than harm. But, as we have been discovering, figuring out that a treatment will be beneficial for the patient is much harder than practitioners of modern medicine ever imagined. To prescribe a medication, the physician really should determine that it is the best available treatment—the drug of choice. This, however, is exactly what physicians cannot be expected to know about their patients.
Beyond Prettiness: Death, Disease, and Being Fat
Authors: Veatch Robert M
Published: November 2023

The guidelines for so-called ideal weight were prepared by the National Institutes of Health. They don’t claim to be concerned about prettiness. They need to have health-related reasons for considering fat people overweight and superskinny people sick. They believe that being overweight is bad for your health and that when something is bad for your health it is bad for you. Hence, the other two reasons people might be concerned about weight— mortality and morbidity, that is, death and poor health.
Health Insurance: The Case for Multiple Lists
Authors: Veatch Robert M
Published: November 2023

The claim is that, in the era of the new medicine, justice will require not only that health insurance be universal, but that different insurance packages will offer different services. Consumers of health insurance will have to be able to pick the package that includes the best mix of services for them. They may pick high-tech medical services rich with organ transplants and artificial organs, but correspondingly light on some other services—perhaps psychological counseling or nursing care. Or they may pick a plan with hospice services, but no experimental cancer chemotherapy. The project for this chapter is to make the moral case for this arrangement, the case that, rather than being unfair because the lists are different, such multiple lists are a moral necessity for a system to be equitable.
Why Hospice Care Should Not Be a Part of Ideal Health Care: I The History of the Hospice
Authors: Veatch Robert M
Published: November 2023

One important development in health care in the past few decades is the emergence of the hospice as an approach to caring for people with critical and terminal illness. Although it might seem odd, I want to suggest that the hospice should not be part of ideal health care. In this and the next chapter I will try to show why a hospice does not fit as part of postmodern medicine.
Clinical Practice Guidelines and Why They Are Wrong
Authors: Veatch Robert M
Published: November 2023

As long as benefits and harms were assumed to be objective and knowable by clinicians independent of individual patient values, people believed that competent clinicians drawing on competent medical science could determine how much good each medical treatment would produce for each patient. Of course, not all outcomes were guaranteed, but based on probabilities, clinicians thought they could predict the likely outcome for each patient and, based on this calculation, decide what was best for the patient.
Prescriptions for the Mind
Authors: Paris Joel
Published: November 2023

The practice of psychiatry has undergone great changes in recent years. In this book, Joel Paris, MD, a veteran psychiatrist, provides a fluently written and accessible "state-of-the-field" assessment. Himself a clinician, researcher, and teacher, Paris focuses on the most striking change within the field - the diverging roles of psychopharmacology and psychotherapy in contemporary practice. Where once psychiatrists were trained in Freudian psychoanalysis - which involved, more than anything else, talking - current pressures in mental health practice, including those imposed by managed care, are leading psychiatrists to treat more and more of their patients exclusively with medication, which is cheaper and faster. At the same time, psychotherapy is increasingly not being taught to new psychiatrists-in-training, even though, as Paris reveals, there is scientific evidence that both talk therapies and medication can play an important role in the treatment of mental illness. These developments are occuring against a backdrop of exploding research in the genetics and neurobiology of mental illness that will continue to drive the field. Paris ends by contemplating how going forward psychiatry can best respond to all these forces and proposes a team-based approach to mental health care. The book will appeal both to specialists and nonspecialists, particularly psychiatric residents and fellows, medical students considering specialization in psychiatry, clinical psychologists, social workers, and general readers, especially consumers of mental health services.
Psychiatric Drugs: Miracles and Limitations
Authors: Paris Joel
Published: November 2023

Drugs are an essential part of the practice of psychiatry. Over the course of a lifetime, I have seen medication work real miracles in treating mental illness. I can also remember the ‘‘bad old days’’ when effective drugs were unavailable (or not prescribed).
The Ethics of Surgery as a Business
Authors: Jones James W , McCullough Laurence B , Richman Bruce W
Published: November 2023

Somehow, calling medicine a business strikes a wrong chord, one that might even suggest a pejorative association. “Profession” seems at first more appropriate, implying that physicians are specially educated and reliably conform to ethical standards of behavior. But don’t we apply these terms to the oldest profession, or to “professional” athletes? Perhaps medicine can better be thought of as a calling, a calling to a well-compensated secular priesthood of health.
Challenges to Medical Professionalism: Assaults From Within and Without
Authors: Jones James W , McCullough Laurence B , Richman Bruce W
Published: November 2023

Physicians confront challenges to their medical professionalism almost daily, emerging from inside and outside the medical establishment. Physicians’ ethically effective reactions to these assaults obligate them to understand the nature of professional responsibility. Many physicians believe that the concept of medicine as a profession was first introduced to Western culture by the authors of the Hippocratic Oath and its accompanying texts. This belief is complemented by the comforting assumption that the ideals of medical professionalism have reached contemporary physicians in an uninterrupted tradition of more than two millennia. These associated beliefs have become ritualized in the nearly universal adoption of some version of the Hippocratic Oath at medical school graduations and, more recently, at “white coat” ceremonies, where first-year medical students are solemnly inducted into their professional apprenticeship.
Cathedrals of Science : The Personalities and Rivalries That Made Modern Chemistry
Authors: Coffey Patrick
Published: November 2023

In Cathedrals of Science, Patrick Coffey describes how chemistry got its modern footing-how thirteen brilliant men and one woman struggled with the laws of the universe and with each other. They wanted to discover how the world worked, but they also wanted credit for making those discoveries, and their personalities often affected how that credit was assigned. Gilbert Lewis, for example, could be reclusive and resentful, and his enmity with Walther Nernst may have cost him the Nobel Prize; Irving Langmuir, gregarious and charming, “rediscovered” Lewis’s theory of the chemical bond and received much of the credit for it. Langmuir’s personality smoothed his path to the Nobel Prize over Lewis. Coffey deals with moral and societal issues as well. These same scientists were the first to be seen by their countries as military assets. Fritz Haber, dubbed the “father of chemical warfare,” pioneered the use of poison gas in World War I-vividly described-and Glenn Seaborg and Harold Urey were leaders in World War II’s Manhattan Project; Urey and Linus Pauling worked for nuclear disarmament after the war. Science was not always fair, and many were excluded. The Nazis pushed Jewish scientists like Haber from their posts in the 1930s. Anti-Semitism was also a force in American chemistry, and few women were allowed in; Pauling, for example, used his influence to cut off the funding and block the publications of his rival, Dorothy Wrinch. Cathedrals of Science paints a colorful portrait of the building of modern chemistry from the late 19th to the mid-20th century.
Physical Chemistry in America: Lewis and Langmuir
Authors: Coffey Patrick
Published: November 2023

At the July 1908 meeting of the American Chemical Society in New Haven, Connecticut, two American physical chemists met for the first time. Both were in early stages of their careers: Gilbert Lewis was thirty-three, and Irving Langmuir was twenty-seven. Lewis was already established at MIT’s Research Laboratory for Physical Chemistry. His boss, Arthur Noyes, was serving as MIT’s acting president, and Lewis had been named temporary director of the laboratory. Although Lewis was now doing well at MIT, he had had a difficult start as an instructor at Harvard, a position he had disliked so much that he had abruptly left for a government job in the Philippines. In 1908, Langmuir was still stuck in a low-level teaching position at Stevens Institute of Technology, a Hoboken, New Jersey, engineering school. Both Langmuir and Lewis were veterans of Walther Nernst’s laboratory in Germany. Neither had liked Nernst much, and they almost certainly traded stories about his behavior.
Pathological Science : Langmuir
Authors: Coffey Patrick
Published: November 2023

On 25 January 1950, Irving Langmuir presented a paper to the American Meteorological Society that his diary called the “most important that I have ever given.” He stood before the U.S. experts on weather and climate and claimed that one person, releasing a small amount of silver nitrate once a week in New Mexico, had changed the weather patterns of the entire United States. His evidence was that the rains had followed the same periodicity as the silver nitrate release. Langmuir’s claims were unconvincing to many in his audience, who thought that he had fallen into the kind of trap he had described many times with regard to the work of others, “where there is no dishonesty involved, but where people are tricked into false results by a lack of understanding about what human beings can do to themselves in the way of being led astray by subjective effects, wishful thinking, or threshold interactions.” The meteorologists may not have known his term for this sort of research, but if they had, they might have used it in the discussion period after his talk—”pathological science.”
Scales And Tones 1957–8
Authors: Cook Richard
Published: November 2023

Davis returned home to the US five days before Christmas, and the quintet I 83 was quickly reconvened. Miles had a fondness for the holiday season, and he liked to be in or near his home town at that time of year, so the group had an engagement in Chicago in late December. Before any further recording was done, though, the line-up changed again: John Coltrane returned to the fold.