bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCOR and Oculofaciocardiodental Syndrome
Authors: Hilton Emma , Black, Graeme C M , Bardwell Vivian 
Published: November 2023

Abstract
In 1980, Hayward described a female with canine (cuspid) radiculomegaly associated with congenital cataracts (Hayward, 1980). Further cases of individuals with similar dental anomalies and congenital cataracts were reported by Marashi and Gorlin (1990, 1992). Wilkie et al. (1993) proposed that this phenotype, in combination with distinctive cardiac and facial findings, comprised a novel syndrome and the term oculofaciocardiodental (OFCD) syndrome was recommended to refer to this disorder (Gorlin et al., 1996). Due to recent changes in nomenclature, OFCD syndrome is now referred to as syndromic microphthalmia 2 (MCOPS2; OMIM 300166). However, the term OFCD syndrome is used throughout this chapter. Since it was defined, the condition has been reported around 30 times, exclusively in females. In 2004, Ng et al. demonstrated that presumed null mutations in the X-linked BCL-6 corepressor (BCOR) gene, which encodes BCOR, are responsible for OFCD syndrome (Ng et al., 2004). Since those individuals tested have skewed inactivation in favor of the wild type allele, it is presumed that OFCD syndrome is X-linked dominant with male lethality. In addition to causing OFCD, a missense mutation in BCOR has been described in a single family with MCOPS2 (X-linked recessive Lenz microphthalmia syndrome), suggesting a correlation between mutation type and phenotype.
CTDP1 and Congenital Cataracts, Facial Dysmorphism Neuropathy (CCFDN) Syndrome
Authors: Kalaydjieva Luba , Gooding Rebecca 
Published: November 2023

Abstract
The complex stepwise process of eukaryotic gene expression (Fig. 110–1) is mediated by the “basal transcription machinery,” which consists of RNA polymerase II(RNAPII) and the general transcription factors, all composed of multiple subunits (see Chapter 101). A unique feature of RNAPII is the end structure of its largest subunit, the carboxy-terminal domain(CTD)(Allison et al., 1985). The CTDconsistsofheptameramino acid repeats, with serine residues at positions 2 and 5 of each consensus repeat unit. The number of CTD repeats correlates with genome complexity, with 26 in yeast, 43 in Drosophila, and 52 in mammals (Allison et al., 1985). The CTD extends like a tail from the main catalytic body of RNAPII, adjacent to the pre-mRNA exit groove (Cramer et al., 2001) (Fig. 110–1), and serves as the platform for the recruitment, assembly, and interaction of multimeric protein complexes involved in the different stages of transcription and in the posttranscriptional modifications of the nascent mRNA (reviewed in Maniatis and Reed, 2002; Hartzog, 2003). The coupling and coordination of these processes is controlled by the changing level and pattern of phosphorylation of the serine 2 and 5 residues in the CTD, a “CTD code,” that specifies the position of RNAPII in a transcription cycle (Kobor and Greenblatt, 2002; Lin et al., 2002a; Maniatis and Reed, 2002; Buratowski, 2003; Hartzog, 2003). In order for RNAPII to be recruited for the assembly of preinitiation complexes (PIC), the CTD has to be dephosphorylated (Chesnut et al., 1992). Subsequent serine 5 phosphorylation occurs in promoter-proximal regions and is necessary for the early stages of transcription, promoter clearance and the recruitment, and activation of the capping enzyme (Cho et al., 1997; Ho et al., 1998). Serine 2 phosphorylation occurs when RNAPII is associated with the coding regions of genes and increases progressively as the transcript moves toward the 3” -end of the gene (Komarnitsky et al., 2000; Cho et al., 2001). Serine 2 phosphorylation is required not only for elongation but also for the assembly of the splicing and polyadenylation machinery (reviewed in Maniatis and Reed, 2002). CTD hyperphosphorylation, mainly of serine 5, has also been suggested to play a role in transcription arrest during mitosis (Xu et al., 2003). The fine balance and selectivity of phosphorylation is under the control of a number of kinases, mostly subunits of transcription factors and members of the family of cyclindependent kinases, which act at different stages of transcription and on different serine residues (reviewed by Kobor and Greenblatt, 2002; Meinhart et al., 2005).
ESCO2 and Roberts Syndrome
Authors: Gordillo Miriam , Vega, Hugo , Jabs Ethylin Wang 
Published: November 2023

Abstract
Roberts syndrome (RBS) or SC phocomelia syndrome (OMIM 286300 and 269000) is a rare autosomal recessive condition characterized by preand postnatal growth retardation, symmetric and mesomelic limb reductions, and craniofacial abnormalities. The upper limbs are more affected than the lower limbs and the hands often present with hypoplasia or agenesis of the thumb and fifth digit. There is correlation between the severity of the limb and craniofacial abnormalities, with cleft lip and palate occurring in patients with very short limbs. The degree of intraand interfamilial phenotypic variability is high. Cells from RBS patients show a characteristic cytogenetic defect, known as premature centromere separation (PCS) or heterochromatin repulsion (HR), consisting of lack of sister chromatid cohesion at heterochromatic regions of all centromeres and the long arm of the Y chromosome.
FOG-2 (now ZFPM2) and GATA-4 and Congenital Heart Disease and Diaphragmatic Hernia
Authors: Slavotinek Anne M 
Published: November 2023

Abstract
This chapter describes the human and murine Fog-2 and Gata-4 genes and their role in cardiac development. The genes are introduced together and then discussed separately in greater depth with detailed sections on human mutations.
PTF1A and Pancreas and Cerebellar Agenesis
Authors: Minton Jayne A L , Hattersley Andrew T 
Published: November 2023

Abstract
Pancreatic and cerebellar agenesis is a discrete subgroup of patients who have permanent neonatal diabetes as a result of pancreatic agenesis. Patients with pancreatic and cerebellar agenesis present in the first week of life with diabetes requiring insulin treatment, very low birth weight, and abnormal facies, and are subsequently detected as having pancreatic exocrine failure and pancreatic aplasia. Neurological features include central hypoventilation, optic nerve hypoplasia, developmental delay, and cerebellar aplasia. This clinical syndrome results from homozygous mutations in the gene (PTF1A) encoding the pancreatic transcription factor 1A. This confirms that in man, as in animal models, PTF1A has a critical role in early pancreatic and neurological development.
TCOF1 (Treacle) and the Treacher Collins Syndrome
Authors: Dixon Jill , Trainor, Paul A , Dixon Michael J 
Published: November 2023

Abstract
Treacher Collins syndrome (TCS; OMIM 154500, also known as mandibulofacial dysostosis and Franceschetti-Zwahlen-Klein syndrome) is a craniofacial disorder that is inherited in an autosomal dominant fashion. TCS occurs with an estimated incidence of 1/50,000 live births (Rovin et al., 1964; Fazen et al., 1967). More than 60% of cases do not appear to have a previous family history and are thought to arise as the result of a de novo mutation (Jones et al., 1975). On the basis that the tissues affected in TCS are derived from the first and second branchial arches, which are populated extensively by cranial neural crest cells (Le Douarin and Kalcheim, 1999), several hypotheses were proposed to explain the cellular basis of this disorder. These early theories included abnormal neural crest cell migration (Poswillo, 1975), improper cellular differentiation during development (Wiley et al., 1983), or an abnormality of the extracellular matrix (Herring et al., 1979). The use of genetic, physical and transcript mapping techniques resulted in the identication of the gene mutated in TCS, designated TCOF1, which was found to encode a low complexity, serine/alanine- rich, nucleolar phosphoprotein that was named Treacle (The Treacher Collins Syndrome Collaborative Group, 1996). More recently, the integration of molecular biology, cell biology, mouse genetics, and experimental embryology has provided novel insights into the molecular pathogenesis of TCS.
CUL7 and the 3M Syndrome
Authors: Huber Céline , Cormier-Daire Valérie 
Published: November 2023

Abstract
3M syndrome is an autosomal recessive condition characterized by severe pre- and postnatal growth retardation with normal endocrine function, facial dysmorphism, large head circumference, and normal intelligence. Skeletal changes include long slender tubular bones and tall vertebral bodies. Using a homozygosity mapping strategy, we have mapped the disease locus gene on chromosome 6p21.1, and considered CUL7 (Cullin 7) as a candidate gene based on a knock- out Cul7−/− mice. Indeed, Cul7−/− embryos are characterized by intra- uterine growth retardation (IUGR), with a placenta of reduced size at late gestational age.
An Introduction to the Mechanisms of Cell Cycle Regulation and Apoptosis
Authors: Vermeulen Katrien , Bockstaele Dirk R Van , Tendeloo, Viggo F I Van , Berneman Zwi N 
Published: November 2023

Abstract
The cell cycle is controlled by numerous mechanisms ensuring correct cell division, that is, regulation of cyclin-dependent kinases (CDKs) by cyclins, CDK inhibitors (CKIs) and phosphorylating events. The quality checkpoints activated after DNA damage are also discussed. The complexity of the regulation of the cell cycle is also re8ected in the different alterations leading to aberrant cell proliferation and development of cancer.
MYCN and the Feingold Syndrome
Authors: Bokhoven Hans Van , Brunner Han G 
Published: November 2023

Abstract
Feingold syndrome (FS) is a dominantly inherited syndrome with apparently full penetrance and variable clinical expression. Its most consistent features are microcephaly, with mental retardation in half of these cases, brachymesophalangy, clinodactyly, syndactyly of toes and short palpebral ssures. Gastrointestinal atresias are also frequently observed, mostly manifesting as esophageal atresia/tracheo-esophageal stula (EA/TEF). The MYCN gene on chromosome 2p23–p24 has been identied as the culprit in this syndrome. Mutations include complete gene deletions, nonsense mutations, frameshifting mutations, and amino acid substitutions at positions that are crucial for DNA-binding of the protein. All these mutations are predicted to yield a null allele, indicating that haploin suficiency is the disease mechanism for FS. Strikingly, MYCN gene ampli cation and overexpression is found in a number of tumors, for example, neuroblastomas, and is generally associated with poor prognosis. Such tumors exhibit the opposite cellular phenotype to that observedinFSpatientsorinNmycknockoutmice.Thereisconvincingevidenceindicating that MYCN/N-myc dosage is critically important for cell proliferation and differentiation. Up-regulated MYCN expression promotes tumor formation by locking cells into a progenitor-like phenotype. Conversely, down-regulation of MYCN expression results in failure to maintain a compartment of undifferentiated, proliferating progenitor cells, resulting in hypoplastic organ structures.
Fanconi Anemia
Authors: Vrugt Henri J Van De , Grompe Markus 
Published: November 2023

Abstract
Fanconi anemia (FA) is a genetically heterogeneous disorder with the clinical features of congenital malformations reminiscent of the VACTERL association, progressive bone-marrow failure, and cancer predisposition. FA cells are characterized by increased sensitivity to DNA cross-linking agents, and FA has thus traditionally been classified as a DNA repair disorder. To date, 13 distinct complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, and O) have been identified and all of the corresponding genes (FANCA, FANCB, etc.) have been isolated. FA is usually autosomal recessive, but one X-linked form exists. The FANCD1 gene is identical to the familial breast cancer gene BRCA2, and multiple biochemical and genetic interactions of the BRCA1 and BRCA2 genes with FA genes have been found. This has given rise to the concept that the FA and BRCA proteins form a genome maintenance network. This FA/BRCA pathway is activated during normal DNA replication and after DNA damage. The majority of FA proteins interact in a multisubunit FA core complex, which acts to monoubiquitinate the FANCD2 protein. Mono-ubiquitinated FANCD2 interacts with BRCA2 in chromatin to protect cells from replication-associated DNA damage.
FGD1 and Faciogenital Dysplasia (Aarskog–Scott Syndrome)
Authors: Gorski Jerome L 
Published: November 2023

Abstract
FGD1 mutations result in faciogenital dysplasia (FGDY; Aarskog–Scott syndrome), an X-linked recessive multiple congenital anomaly syndrome. Skeletal anomalies dominate the FGDY phenotype. Cardinal clinical features include a characteristic set of craniofacial and skeletal anomalies, disproportionate acromelic short stature, delayed skeletal maturation, and urogenital malformations. FGD1 encodes a guanine nucleotide exchange factor (GEF) that speci’cally activates Cdc42, a Rho guanosine triphosphatase (GTPase) that is involved in cell signaling and the regulation of the actin cytoskeleton, vesicular transport, and gene expression. The FGD1 protein is composed of multiple signaling motifs including a Src homology 3–binding domain, a GEF domain, a zinc-’nger FYVE domain, and two pleckstrin homology (PH) domains. By activating Cdc42, FGD1 stimulates cells to reorganize their actin cytoskeleton and form ‘lopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis, and cellular differentiation.
NPR2 and Acromesomelic Dysplasia, Type Maroteaux
Authors: Warman Matthew L , Olney Robert C 
Published: November 2023

Abstract
A signaling pathway that is active during endochondral ossi2cation, involving C-type natriuretic peptide [CNP, gene name natriuretic peptide precursor C (NPPC)] and the natriuretic peptide receptors 2 and 3 (NPR2, NPR3) is essential for normal skeletal growth. The importance of this pathway was 2rst identi2ed in mice with naturally occurring and/or targeted mutations in NPPC and NPR3 (Jaubert et al., 1999; Matsukawa et al., 1999; Chusho et al., 2001). Humans with the autosomal recessive, skeletal dysplasia, acromesomelic dysplasia, type Maroteaux (AMDM) have NPR2 mutations, which cause a complete loss of receptor function (Bartels et al., 2004); interestingly, heterozygous NPR2 mutation carriers have no evidence of skeletal dysplasia, but are shorter than noncarriers (Bartels et al., 2004; Olney et al., 2006). The upstream and downstream participants/pathways involved in CNP/NPR2 signaling are incompletely understood, but thus far include cGMP-mediated pathways, ERK1/2 within the mitogen-activated protein kinase (MAPK) pathway and possibly the transcription factor SOX9 (Chikuda et al., 2004; Yasoda et al., 2004; Krejci et al., 2005).
GPR56 and Bilateral Frontoparietal Polymicrogyria
Authors: Piao Xianhua , Walsh Christopher A 
Published: November 2023

Abstract
Polymicrogyria is the malformation of the cerebral cortical development, in which the brain surface is irregular and the normally convoluted gyri are replaced by numerous (poly) and notice- ably smaller (micro) gyri. Bilateral frontoparietal polymicrogyria (BFPP) is an autosomal recessively inherited polymicrogyria syndrome. Individuals with BFPP suffer from mental retardation, motor developmental delay, seizures, dysconjugate gaze, and clumsy movement. Magnetic resonance imaging (MRI) demonstrated symmetric polymicrogyria with anterior regions most severely affected, as well as ventriculomegaly, bilateral white matter signal changes, and small brain stem and cerebellar structures. The BFPP locus was mapped to chromosome 16q12-21, and the causative gene isGPR56. GPR56 is an orphan G protein–coupled receptor (GPCR). The function of GPR56 remains elusive. The diagnosis of BFPP is established on the bases of clinical presentation, brain MRI 2ndings, and genetic testing.
LIS1 and DCX1 and Classical Lissencephaly
Authors: Gleeson Joseph G 
Published: November 2023

Abstract
Classical lissencephaly (LIS) is either a sporadic autosomal disorder or an X-linked dominant disorder that affects approximately 1:40,000 individuals. It is characterized by the presence of a severely thickened cerebral cortical gray matter with widely spaced gyri and sulci. Diagnosis of LIS is made by the characteristic magnetic resonance imaging (MRI) appearance of the brain. Associated clinical features include significant mental retardation, intractable epilepsy, and shortened life expectancy. Syndromes related to LIS include the double cortex syndrome, a less severe genocopy syndrome; lissencephaly with cerebellar hypoplasia; polymicrogyria; and cobblestone (or type II lissencephaly) with associated congenital muscular dystrophy and eye disease. Positional cloning identified the LIS1 (lissencephaly-1) gene on chromosome 17p13.3 and the doublecortin (DCX) gene on chromosome Xq22.3–23 as independently responsible for cases of LIS. The two genes encode for microtubule-associated proteins and are critical for neuronal migration. Although their exact role in migration remains unclear, they appear to function with dynein, the main minus end–directed microtubule motor, to both leading process stabilization and nuclear translocation. Submicroscopic deletions or intragenic LIS1 mutations are associated with LIS, whereas larger deletions are associated with Miller–Dieker syndrome (MDS). Most DCX mutations are single-base mutations leading to amino acid substitutions or frameshift mutations. Genetic counseling depends largely on the results of mutation analysis, and prenatal diagnosis is available. Treatment consists of supportive measures and seizure prevention, with a focus on quality of life.
The Molecular Basis of Joubert Syndrome and Related Disorders
Authors: Zimbric Michael R , Gleeson Joseph G 
Published: November 2023

Abstract
INTRODUCTION
Joubert syndrome and related disorders (JSRD) are autosomal recessive conditions that are characterized by cerebellar vermis hypoplasia (CVH), diffuse hypotonia, developmental delay, abnormal respiratory patterns in the neonatal period, and oculomotor apraxia. The key neuroradiological finding in JSRD is the presence of a complex malformation of the hind- brain–midbrain junction, CVH, thick and maloriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. On axial magnetic resonance imaging at the level of the junction of the cerebellum and midbrain, the malformation is associated with an unusual appearance resembling a molar tooth—the so-called molar tooth sign (MTS). Along with these typical features, the eyes, kidneys, liver, and other organs may be affected. Other noted features have included postaxial polydactyly, soft tissue tumors of the tongue, encephalocele, and behavioral abnormalities suggestive of autism. The genetic basis of JSRD is highly heterogeneous and lies with at least 2ve distinct chromosomal loci: JBTS1–JBTS5. The phenotypes associated with JBTS1 and JBTS3 are largely restricted to the central nervous system (CNS), while JBTS2 shows more varied and severe phenotypes, including retinal and renal involvement. JBTS4 mutations show a milder appearance of the MTS and co-occurrence of nephronophthisis (NPH) and varying neurological symptoms. The known genes encode modular scaffolding proteins of unknown function, and mutations are largely inactivating. The long-term outcome of patients with JSRD is varied but generally involves marked impairment of intelligence, speech deficit, and ataxia of gait, but mild improvements in oculomotor and breathing abnormalities with time. Genetic counseling for JSRD relies upon recognizing the autosomal recessive inheritance pattern and the natural variability of disease. Prenatal diagnosis in at-risk pregnancies is possible with prenatal imaging. Currently, management involves supportive measures along with individualized neuropsychological assessment and screening for other organ involvement. Future efforts may produce refinements in genetic testing strategies.
VPS13B and Cohen Syndrome
Authors: Manson Forbes D C , Chandler, Kate E , Black Graeme C M 
Published: November 2023

Abstract
Cohen syndrome (COH1) (MIM 216550) is an autosomal recessive condition with a distinct clinical phenotype that has been attributed to mutations in the VPS13B gene. The initial report was by Cohen in 1973 who reported a brother and sister and an unrelated patient, with developmental delay and a similar dysmorphic facial gestalt associated with microcephaly, truncal obesity, joint hyperextensibility, hypotonia, and speci2c ophthalmic abnormalities (Cohen et al., 1973). The condition is uncommon with reported cases worldwide numbering hundreds rather than thousands and is one of several autosomal recessive conditions overrepresented in the Finnish population where the relatively homogeneous phenotype enables it to be better delineated (Norio, 2003). Outside Finland, Cohen syndrome shows variability and the precise diagnostic criteria continue to be an area of contention. However, the key features include mild–moderate developmental delay, microcephaly, hypotonia, myopia, retinal degeneration, and neutropenia. VPS13B is a large gene of 62 exons that spans over 850 kb of chromosome 8q22-q23. The gene is a member of a family of four human genes (VPS13A-D) that share homology to the Saccharomyces cerevisiae Vps13p protein. Chorein, the protein product of VPS13A (previously named CHAC), is mutated in chorea-acanthocytosis.
Extracellular Matrix and Signaling during Development
Authors: Selleck Scott B , Stringer Sally E 
Published: November 2023

Abstract
There was a time when the biology of the extracellular matrix was considered quite separately from study of signaling or morphogenesis. This was even reMected in the terminology of the 2eld, where “ground substance” was used to refer to the extracellular matrix. “Ground substance” certainly does not evoke images of dynamic pro- cesses that involve interactions between cells and their environment. We now know that it is impossible to understand the biology of multi- cellular organisms without appreciating that cells create the extracellular matrix that surrounds them and that the matrix reciprocally affects virtually all aspects of cellular behavior.
HSPG2 and the Schwartz–Jampel Syndrome and Dyssegmental Dysplasia, Silverman–Handmaker Type
Authors: Nicole Sophie , Stum, Morgane , Fontaine Bertrand 
Published: November 2023

Abstract
Schwartz–Jampel syndrome (SJS) (OMIM 255800) and dyssegmental dysplasia, Silverman–Handmaker type (DDSH) (OMIM 224410), are two infrequent human disorders transmitted with an autosomal-recessive mode of inheritance. Both are characterized by abnormal endochondral ossification resulting in skeletal malformations. However, they differ on their degree of severity; DDSH is lethal, unlike SJS. In addition, SJS is characterized by a permanent muscle stiffness (myotonia) owing to a severe muscle hyperexcitability, which has not been reported in DDSH. Both disorders have been linked to loss of function mutations in the gene encoding perlecan, the major heparan sulfate (HS) proteoglycan (HSPG) of basement membranes (BMs) (see Chapter 163). The functions of perlecan have been in part elucidated, and animal models with perlecan deficiency are available, which suggest SJS and DDSH pathophysiological models.