bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction to Paired-Box Genes
Authors: Petrou Petros P , Gruss Peter
Published: November 2023

The paired box–containing (Pax) genes comprise a family of highly conserved transcriptional regulators that play essential roles in diverse processes of early animal development and cell-fate speci)cation. The discovery of their characteristic feature, the paired box, dates back to the extensive systematic mutagenesis screen performed in the fruit %y Drosophila melanogaster (Nüsslein-Volhard and Wieschaus, 1980). The isolation and subsequent cloning of the genes affected by mutations, resulting in defects in primary body patterning and segmentation, revealed that many of them encoded transcriptional regulators that share common amino acid motifs. The paired box was named after the pair-rule gene paired and identi)ed as a common sequence motif shared by paired and the two genes of the gooseberry locus of Drosophila, gooseberry-proximal (gsb-p) and gooseberry-distal (gsb-d) (Bopp et al., 1986). These same genes displayed an additional sequence pattern of about 180 bp, which was identi)ed in the genes underlying homeotic transformations in the %y and therefore termed the homeobox (McGinnis et al., 1984; Scott and Weiner, 1984). Two further genes, Pox-meso and Pox-neuro, were subsequently identi)ed in Drosophila as paired box–containing genes that, in contrast to paired, did not contain a homeobox (Bopp et al., 1989). The discovery of the paired box in Drosophila was followed by an extensive search for related genes in the genomes of other species. Based on their sequence similarity to the Drosophila genes, paired box–containing genes were subsequently identi)ed in a variety of organisms. Nine paired box–containing genes, denoted Pax1 to Pax9, have so far been identied in the mouse and human (reviewed in Dahl et al., 1997; Mansouri et al., 1999; Underhill, 2000; Chi and Epstein, 2002), which, in contrast to Hox genes (Kessel and Gruss, 1990), are not organized in chromosome clusters. Moreover, paired box–containing genes have also been discovered in the genomes of other metazoans, such as nematodes and arthropods, as well as in more primitive organisms such as hydrozoa, porifera, anthozoa, and placozoa (Sun et al., 1997; Hoshiyama et al., 1998; Groger et al., 2000; Hadrys et al., 2005). Thus, the Pax family comprise genes that arose very early in evolution and are highly conserved throughout phyla.
PAX2 and the Renal–Coloboma Syndrome
Authors: Eccles Michael R
Published: November 2023

PAX2, the second member of the PAX gene family, is located in a generich region of human chromosome 10, near the boundary of bands q24 and q25 (Eccles et al., 1992; Stapleton et al., 1993; Narahara et al., 1997). PAX2 is expressed in fetal brain, spinal cord, eye, ear, urogenital tract, pancreas, and kidney (Dressler et al., 1990; Nornes et al., 1990; Eccles et al., 1992; Terzic et al., 1998; Ritz-Laser et al., 2000; Tellier et al., 2000). Following birth, PAX2 expression declines in many tissues (Dressler and Douglass, 1992; Eccles et al., 1992), but it remains expressed in parts of the urogenital tract (Winyard et al., 1996) and in the endocrine pancreas where it regulates glucagon gene expression (Ritz-Laser et al., 2000).
Introduction to Forkhead Genes
Authors: Miura Naoyuki , Xue, Xiaodong , Itakura Tatsuo
Published: November 2023

Finding a mutant in the organism is always a key factor for identi)cation of a gene involved in a biological function. One Drosophila mutant, which has a homeotic transformation called fork head, thus opened the way to identify the causative genes for several inherited diseases with pleiotropic phenotypes. In 1989 and 1990, two genes were identi)ed: one, fork head was identi)ed through %y genetics while the other, HNF-3α (hepatocyte nuclear factor-3α) was identi)ed by biochemical puri)cation. A conserved region encoding 100 amino acids found in the two genes was named “forkhead.” More than 100 forkhead genes have been cloned, from yeast to humans. Recently, forkhead proteins were renamed Fox (Forkhead box). They act as either transcriptional activators or transcriptional repressors. Gene knockout technology has been applied in mice to this family of genes to clarify the developmental roles of each gene. Concerted, positional cloning has identied several forkhead genes as the causative genes for human and rodent inherited disorders. These results indicate that Fox genes play important roles as transcriptional regulators in cell proliferation, cell-fate determination, and cell differentiation during development and also are the causative genes for human inherited disorders with pleiotropic phenotypes.
FOXE1 and Choanal Atresia, Cleft Palate, and Thyroid Agenesis
Authors: Castanet Mireille , Polak Michel
Published: November 2023

The thyroid transcription factor-2 (TTF-2), more recently called FOXE1 (forkhead box E1), plays a crucial role in the development of ectodermand endoderm-derived structures, including the thyroid gland. Mice with complete disruption of the Titf2 gene exhibit either a sublingual or completely absent thyroid gland, together with cleft palate, thereby strongly suggesting a role for FOXE1 in promoting the migration process or in thyroid follicular differentiation as well as in palatal closure. The phenotypic manifestations of the knockout mice are consistent with the expression pattern of TTF2, which is found (1) in most of the foregut endoderm, including thyroid anlage, (2) in the craniopharyngeal ectoderm involved in palate formation, and (3) in the Rathke’s pouch. In humans, some homozygous missense mutations located in the forkhead domain of FOXE1 have been identi)ed in patients exhibiting a “complete” or “partial” Bamforth syndrome, characterized by thyroid agenesis, cleft palate and spiky hair, with choanal atresia and bi)d epiglottis in the complete phenotype. Taken together, these observations point to a key role for FOXE1 in human thyroid and palatal development. However, recent reports show that TTF2 mutations are rare in patients with thyroid dysgenesis and/or cleft palate, suggesting the involvement of other maybe downstream target genes. Therefore, more studies are needed to elucidate the genetic basis of Bamforth syndrome.
TBX1 and the DiGeorge Syndrome Critical Region
Authors: Klewer Scott E , Runyan, Raymond B , Erickson Robert P
Published: November 2023

Congenital cardiovascular malformation is the most common class of birth defects and one of the three most common causes of death in the )rst year of life (Rubin et al., 1985). Abnormal gene dosage is the best understood genetic cause of congenital heart defects (CHDs). The most common genetic cause of CHDs is trisomy-21 (Down syndrome), which affects approximately 1 in 1000 fetuses and is associated with a 40% incidence of cardiac defects (Adams et al., 1981). Inappropriate gene dosage caused by gene deletions is also associated with congenital heart disease. Children with DiGeorge syndrome (DGS) or sequence, who display a recognizable spectrum of craniofacial anomalies, abnormal morphogenesis of the cardiac out%ow tract and great vessels (aorta, subclavian, pulmonary arteries), and thymic and parathyroid defects often have microdeletions of chromosome 22q11 (Driscoll et al., 1993). Identical chromosome 22q11 deletions have been identi)ed in patients with velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CAFS), and isolated CHDs (Goldmuntz et al., 1998). Deletion of this region on chromosome 22, called the “DiGeorge critical region” (DGCR), is the second most common known genetic cause of congenital heart disease (Goodship et al., 1998). The heterogeneous clinical manifestations of these 22q11 deletion syndromes have captured the interest and attention of clinical and molecular geneticists hoping to dissect the genetic basis of this human chromosomal haploinsuf)ciency.
TBX22 and X-Linked Cleft Palate and Ankyloglossia
Authors: Pauws Erwin , Stanier Phillip
Published: November 2023

clefts of the lip and/or palate are among the most common birth defects worldwide. Despite intensive effort, there is still a limited understanding of the underlying molecular etiology. One exception to this is X-linked cleft palate and ankyloglossia (CPX), where mutations have been described in the gene encoding the transcription factor TBX22. CPX patients are typically male with a complete cleft of the secondary palate in conjunction with ankyloglossia. Obligate female carriers frequently have ankyloglossia but only occasionally a cleft palate (CP). CPX can result from a spectrum of missense, nonsense, splice site, and frameshift mutations in TBX22. Analysis of random CP cases, unselected for X-linked inheritance or the presence of ankyloglossia, indicates that approximately 4% of all nonsyndromic CP patients have TBX22 mutations. Molecular studies indicate that the aberrations found in TBX22 most likely result in a complete loss of function. Missense mutations that have been described are exclusively found in the T-box domain and are likely to lead to impaired binding to DNA target sequences. In this chapter we describe the clinical background of CPX, the spectrum of TBX22 mutations with relevance to phenotype, and the putative role of TBX22 in developmental pathways involved in palatogenesis.
The SOX Genes in Development and Disease
Authors: Hosking Brett , Koopman Peter
Published: November 2023

The ordered progression of cellular events occurring during embryonic development is ultimately controlled by changes in gene expression resulting from the action of a class of regulatory molecules known as transcription factors. These proteins typically bind to DNA and, in concert with other transcription factors or cofactors, control the activity of individual genes or groups of genes. Transcription factors can perform this task in a number of ways. They may activate or suppress transcription directly, or control the availability of genes for transcription by causing structural changes in the DNA, or they may alter the organization of the chromatin )ber itself.
Mechanisms of Regulated Gene Transcription
Authors: Jepsen Kristen , Perissi Valentina , Lunyak Victoria , Rosenfeld, Michael G , Glass Christopher K
Published: November 2023

Precisely regulated patterns of gene expression are crucial for nor-mal development and homeostasis. Orchestrating these patternsrequires the coordination of numerous regulatory events and mecha-nisms in order to mediate both the repression and activation of specific target genes at specific times and places. Studies of the molecular basis for gene transcription have linked the processes of transcription initiation, elongation of nascent transcripts, messenger RNA (mRNA) splicing, termination, and polyadenylation, as well as the control of RNA stability (reviewed in Maniatis and Reed, 2002). Transcription requires the actions of families of complexes essential for the function of RNA polymerase II, including TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH (reviewed in Butler and Kadonaga, 2002). The “general” transcription factors position and orient Pol II on the canonic elements, determining the initiation site.
IGF2, H19, p57KIP2 (CDKNIC), and LIT1 (KCNQ1OT1) and the Beckwith–Wiedemann Syndrome
Authors: Debaun Michael R , Feinberg Andrew P
Published: November 2023

Beckwith–Wiedemann syndrome (BWS) (OMIM 130650) is a dis-order of prenatal overgrowth, birth defects, and predisposition to cancer, and therefore of great interest in understanding embryogenesis and malignancy. BWS is also a paradigm to evaluate the role of epi-genetics, that is, heritable information not embodied within the DNA sequence itself. Genomic imprinting is a parent of origin-specifi c mark in the gamete, which leads to preferential expression of a specific parental allele in somatic cells of the offspring. Imprinted genes are often marked by differential DNA methylation of the two parental alleles. Through molecular characterization of BWS the fi rst epigenotype–phenotype relationship in human genetics has been described. Several genes in an imprinted genomic domain of 11p15 are involved in the dis-order, with insulin-like growth factor 2 (IGF2) and H19 associated with cancer and p57KIP2 and long intronic transcript 1 (LIT1), an antisense RNA, linked to overgrowth and midline abdominal wall defects. There also are likely additional genes involved in the pathogenesis of BWS.
DNMT3B and the Immunodeficiency–Centromeric Instability–Facial Anomalies Syndrome
Authors: Mccandless Shawn E , Cassidy Suzanne B
Published: November 2023

ICF syndrome (OMIM 242860) is a rare recessive autosomal disease characterized by variable combined immunodeficiency (I), centromeric instability (C) and facial anomalies (F) (Hultn, 1978; Tiepolo et al., 1978, 1979). The dysmorphic facial features include hypertelorism, low-set ears, micrognathia, a 8at nasal bridge, and an epicanthus. The unusually decondensed and juxtacentromeric heterochromatin of chromosomes 1 and 16 and, less frequently, chromosome 9 is abnormally hypomethylated in all ICF tissues. The hypomethylated classical satellite 2 is the preferential breakpoint for the deletions and duplications of chromosome arms observed in the lymphocyte cells of patients with ICF. This syndrome can be diagnosed on the basis of these characteristic chromosome abnormalities and the variable immunodeficiency associated with life-threatening infections. The ICF locus has been mapped to 20q11-13, and mutations have been observed in the DNMT3B gene in several patients. The DNMT3B (ICF) gene is required for de novo methylation and normal development.
BCOR and Oculofaciocardiodental Syndrome
Authors: Hilton Emma , Black, Graeme C M , Bardwell Vivian
Published: November 2023

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.
L1CAM and X-Linked Hydrocephalus
Authors: Schrander-Stumpel Connie , Fryns Jean-Pierre
Published: November 2023

Mutations in the L1 cell adhesion molecule (L1CAM) gene encoding for the neural (L1) cell adhesion molecule L1CAM, located at Xq28, result in a varying clinical spectrum. Manifestations range from lethal congenital hydrocephalus in males (X-linked hydrocephalus or hereditary stenosis of the aquaductus of Sylvius [HSAS], OMIM 307000) to mild to moderate mental retardation combined with spastic paraplegia (with or without hydrocephalus on brain imaging): MASA syndrome (mental retardation, aphasia or slow speech development, shufMing gait or spastic paraplegia, and adducted thumbs; OMIM 303350) (Schrander-Stumpel and Vos, 2006). X-linked spastic paraplegia (SPG1, OMIM 312900) is included in the spectrum, as is “L1 syndrome” (OMIM 308840), which includes the X-linked agenesis of the corpus callosum and mental retardation with clasped thumb.
FRAS1 and FREM2 and the Fraser Syndrome
Authors: Smyth Ian , Scambler Peter
Published: November 2023

Fraser syndrome (FS) is a recessive multisystem disorder characterized by cryptophthalmos, cutaneous syndactyly, renal defects, and a range of other developmental abnormalities. More than 17 years ago the family of four mapped mouse “blebs” mutants were proposed as models of this disorder, given their striking phenotypic overlaps. The blebs mutants all demonstrate intrauterine blistering. Two FS and four bleb genes have been cloned revealing a family of three large extracellular matrix (ECM) proteins (Fras1, Frem1, Frem2) and an intracellular adapter protein [glutamate receptor interacting protein (Grip1)] which are required for normal epidermal adhesion early in development. FRAS1 and FREM2 are the human FS genes, Fras1, Frem1, Frem2, and Grip1 are mutated in blebs mice. Fras1 and Frem2 require Grip1 for presentation at the apical surface of keratinocytes, whereas Frem1 is a protein secreted from the dermal cell layer. The proteins interact with collagens in the epidermal basement membrane (BM) but it is uncertain whether this is a direct or indirect relationship. The Fras/Frem/Grip proteins have also been shown to play a crucial role in the development of the kidney and maintenance of its subsequent structural integrity.
EFNB1 and EFNA4 in Craniofrontonasal Syndrome and Craniosynostosis
Authors: Twigg Stephen R F , Wilkie Andrew O M
Published: November 2023

Craniofrontonasal syndrome (CFNS) has a distinctive pattern of presentation in which females are characteristically affected, whilst males are fewer in number and tend to have a milder phenotype. CFNS is not transmitted to the sons of male carriers but invariably is to their daughters, supporting an X-linked mode of transmission. The markedly milder phenotype in males than females presents a paradox which has only recently been resolved with the discovery that mutation of EFNB1, which maps to Xq13.1 and encodes a protein involved in cell recognition (ephrin-B1), is responsible for most cases of CFNS. Analysis of the knockout (KO) Efnb1 mouse, in which heterozygous females have a more severe phenotype than either hemizygous males or homozygous females, has led to a model of pathogenesis whereby the process of X-inactivation leads to aberrant sorting of ephrin-B1 wild type and mutant cells in the heterozygous female, with the result that ectopic tissue boundaries are formed. This process has been termed “cellular interference” and cannot occur in hemizygous males. The generally milder phenotypes observed in males suggest that ephrin-B1 function is redundant in most tissues where it is expressed.
ANKH and Craniometaphyseal Dysplasia
Authors: Nürnberg Peter , Tinschert Sigrid
Published: November 2023

Craniometaphyseal dysplasia (CMD) is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Affected individuals display highly variable features ranging from barely discernible anomalies to severe nasal obstruction, compression and functional impairment of cranial nerves, and increased intracranial pressure. An autosomal- dominant form of the disorder (CMDD; OMIM 123000) was linked to chromosome 5p15.2-p14.1 within a region harboring the human ortholog of the mouse progressive ankylosis (Ank) gene. The gene codes for a protein with a putative role in the transport of inorganic pyrophosphate (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralization, and bone resorption. Sequencing of the 12 exons of ANKH revealed six different heterozygous mutations in several unrelated CMD patients, including sporadic cases with supposed autosomal-recessive CMD (CMDR; OMIM 218400). The mutations occurred at highly conserved amino acid residues presumed to be located in the cytosolic portion of the multipass transmembrane ANK protein. The dominant effect of the ANKH mutations in CMD patients contrasts with the recessive character of the truncating mutation in the ank mouse and suggests a gain of function or a dominant-negative effect as the molecular basis of the CMD pathology. So far, no phenotype–genotype correlation is evident.
LMBR1 and Acheiropodia and Preaxial Polydactyly
Authors: Tsipouras Petros , Kilpatrick Michael W
Published: November 2023

Acheiropodia (OMIM 200500) is a genetically inherited limb malformation detected at birth. The condition was initially described in 1929 (Peacock, 1929) and since then, several reports have delineatedits clinical and radiographic phenotype(Toledoand Saldanha, 1969, 1972; Marcallo et al., 1979; Grimaldi et al., 1983; Fett-Conte and Richieri-Costa, 1990; Lemos Silveira and Freire-Maia, 1998). Recently, Acheiropodia was mapped on 7q36 (Escamilla et al., 2000; Ianakiev et al., 2001) in a region overlapping with that of Preaxial polydactyly (PPD, OMIM 1745000) (Heutink et al., 1994; Tsukurov et al., 1994). The two conditions albeit phenotypically distinct appear to originate from structural disruptions of the C7orf2 gene locus (Ianakiev et al., 2001), which encodes the orthologue of the murine Limb region 1 (Lmbr1) gene (Clark et al., 2000). While a null mutation of the C7orf2 gene transcript results in Acheiropodia, PPD probably results from the inability of the same locus to function as a cis-acting regulator for the Sonic hedgehog (SHH) gene (Lettice et al., 2002).
Talking about Literature
Authors: Hayes Kevin J
Published: November 2023

Jefferson traveled to Versailles in May 1785 to assume his position as American minister to the Court of France. Presenting his credentials to King Louis XVI and the Comte de Vergennes, he underwent what he called the “ceremonies usual on such occasions.” His matter-of-fact description of the experience shows how little he cared for such pomp. Neither his contemporary correspondence nor his subsequent reminiscences reveal anything further about this visit to Versailles. However, there was one aspect of becoming ambassador Jefferson frequently recalled. Informing French acquaintances and officials of his new position in the forthcoming weeks, he had to endure the same question time and again. “C’est vous, Monsieur, quire place le Docteur Franklin?” they asked.
Summer of ‘86
Authors: Hayes Kevin J
Published: November 2023

Jefferson’s springtime activities in London helped shape his summertime activities in Paris. After returning to France in May, he caught up his correspondence, writing several friends to tell them about his trip and inform them of his return. To one he described the painterly skill of John Trumbull, who was planning to visit Paris soon, though not as soon as Jefferson imagined. Trumbull did not reach Paris until late July. Before then, Jefferson had much that required his attention, including some unfinished literary business. The friendship he and William Stephens Smith had formed, combined with new contacts in London’s literary world, had given him an idea for marketing Dr. David Ramsay’s History of the Revolution in South Carolina, a problem that had been preying on his mind for months.
Last Days in Paris
Authors: Hayes Kevin J
Published: November 2023

Returning to Paris from the Rhine Valley, Jefferson made up his mind: he would go back to Virginia—not permanently, just for a few months, time enough to bring his daughters home and straighten out his personal and financial affairs. When he had left Monticello in October 1783 to serve as delegate to the Continental Congress, he had planned to be away for only five months. It had now been five years since he had seen home. The third week of November 1788 he wrote Congress to ask for a leave of absence. He argued persuasively that he could make the trip without detriment to his responsibilities as American minister to France. His ministerial duties, he assured Congress, had reached a pause. His most pressing commitments had been fulfilled or would be in a matter of weeks. Most important, he had reached a new consular convention, which he was arranging to have printed. In addition, he had finished composing Observations on the Whale-Fishery, which would also be published soon.
The Anas
Authors: Hayes Kevin J
Published: November 2023

The late eighteenth century was the era of the ana, a time that saw many excellent of memorable sayings from remarkable people. It was the time of James Boswell’s Life of Johnson—”the Ana of all Anas,” Robert Southey called it. It was also the time of Thomas Jefferson’s The Anas, the finest work of its kind in American literature. The Anas contains notes on Jefferson’s conversations during his time as secretary of state. He did not set out to create a literary work while fulfilling his responsibilities in Washington’s cabinet. But as he continued serving as secretary of state, he realized that what Washington and other members of his administration were saying was worth putting down on paper. Jefferson was motivated to create The Anas for much the same reason he was motivated to take detailed notes of the proceedings of the Continental Congress a decade and a half earlier: they were useful at the moment—for recording important political business—but they were also useful in the long run, as a record of the beginnings of American democracy.
Letters from a Virginia Farmer
Authors: Hayes Kevin J
Published: November 2023

Writing to Mann Page in the summer of 1795 to apologize for not joining him in Fredericksburg as they had planned, Jefferson began by listing excuses—”the heat of the weather, the business of the farm”—but he stopped short. Instead of providing any more specific reasons for his absence, he decided to supply a general excuse or, as he put it, “one round reason for all.” He said, “I have laid up my Rosinante in his stall, before his unfitness for the road shall expose him faultering to the world.” Jefferson’s “round reason” is both figurative and literary. The name Rosinante refers to Don Quixote’s superannuated steed. Once again, Jefferson was casting himself in the role of Cervantes’ hero. But no longer was he tilting at windmills: Thomas Jefferson was now Don Quixote in retirement.