bluuebunny/crossref_metadata_2025_split huggingface dataset:
The RAS/MAPK Pathway and the Cardio–Facio–Cutaneous Syndrome
Authors: Rauen Katherine A 
Published: November 2023

Abstract
Cardio facio cutaneous (CFC) syndrome (OMIM 115150) is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic craniofacial features, cardiac defects, ectodermal anomalies, developmental delay, and hypotonia. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo mutations in protein kinases B-Raf, mitogen-activated protein kinase kinase 1 (MEK1), and mitogenactivated protein kinase kinase 2 (MEK2). Activating mutations in K-Ras have also been implicated in causing CFC syndrome, yet its association has to be determined. CFC syndrome has a distinct phenotype, yet shares many overlapping features with other related Ras pathway syndromes, such as Noonan syndrome and Costello syndrome. CFC has characteristic craniofacial dysmorphia, cardiac anomalies, (pulmonic stenosis, atrial septal defects, and hypertropic cardiomyopathy being the most common) and ectodermal anomalies (sparse, curly hair, scant eyebrows and eyelashes, keratosis pilaris, ichthyosis, and nevi). Other features involve the musculoskeletal, ophthalmologic, gastrointestinal (GI), and lymphatic systems. Hypotonia is a consistent ending, and developmental delay ranges from mild to severe. Many patients have a seizure disorder and abnormal brain imaging. The clinical diagnosis of CFC is based on phenotypic /ndings, with molecular con/rmation of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), MEK1, kristen rat sarcoma viral oncogene homolog (MEK2), or KRAS by direct gene sequencing. Current medical management and therapy requires a multidisciplinary team of health care providers and is based on the symptomatology of the individual. Because the Ras/MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that speci/cally target this pathway may merit investigation in this population of patients.
HOXD13 and Synpolydactyly
Authors: Goodman Frances R , Scambler Peter J 
Published: November 2023

Abstract
OXD13 (homeobox D13), the most 5” member of the HOXD gene cluster, encodes a highly conserved transcription factor that plays a crucial role in the development of the autopod; but the molecular pathway in which it acts is poorly understood. Little is known about how its expression is regulated, and none of its target genes or transcriptional cofactors has yet been identified. Synpolydactyly (SPD), the first human birth defect found to be caused by mutations in a HOX gene, is a rare, dominantly inherited malformation of the hands and feet, characterized by soft tissue syndactyly between the third and fourth fingers and between the fourth and fifth toes, with variable digit duplication in the syndactylous web. Most cases result from different-sized expansions of a polyalanine tract in HOXD13”s N-terminal region, and both penetrance and phenotypic severity have been shown to correlate positively with expansion size. The mutant protein appears to interfere functionally with both the remaining wild-type HOXD13 and other 5” HOXD proteins expressed in the developing autopod, acting as a “super” dominant-negative protein. A milder atypical form of SPD, characterized by a distinctive foot phenotype, results from a variety of other HOXD13 mutations, all of which are likely to cause functional haploinsufficiency. In addition, two unusual forms of brachydactyly, distinct from SPD but exhibiting overlap with brachydactyly types D and E, result from specific missense mutations in the HOXD13 homeodomain, which alter rather than abolish DNA binding. The abnormalities in these conditions appear to reHect disturbances of patterning and growth both at the early stage of autopod development in undifferentiated mesenchyme and at a later stage in the chondrogenic cells of cartilaginous bone models. These observations suggest that downstream targets of HOXD13 are likely to include genes with important roles in cell sorting/boundary formation and cell cycle control.
EMX2 and HESX1 and Type I Schizencephaly and Septo-Optic Dysplasia
Authors: Kelberman Daniel , Dattani Mehul T 
Published: November 2023

Abstract
The pituitary gland is a central regulator of growth, reproduction, and homeostasis. During embryogenesis, complex molecular pathways are established to define the development of the pituitary. Given the close anatomical and developmental relationship between the forebrain and anterior pituitary any aberration in this process will impinge not only on the development of the anterior pituitary, but also on the development of other structures, particularly other forebrain structures, the developing eye, and the cerebellum. This suggestion has been borne out by descriptions of the genetic basis of syndromes affecting the pituitary, such as septo-optic dysplasia (SOD). Elucidation of the molecular basis of disorders affecting solely the pituitary and syndromes in which the pituitary is but one component can lead to a better understanding of the complex genetic pathways that result in normal patterning of the forebrain and structures such as the anterior pituitary.
PDX1 and Pancreatic Agenesis and Type 2 Diabetes
Authors: Thomas Melissa K , Habener Joel F 
Published: November 2023

Abstract
Pancreas duodenum homeobox-1 (PDX-1) is a pancreas-specific homeodomain transcription factor that regulates embryonic pancreas development, the expression of genes essential for glucose metabolism, and the differentiation, survival, and function of insulin-producing cells in the endocrine pancreas. Expression of PDX-1 is confined primarily to the developing embryonic pancreas and the adult pancreatic β cells, and PDX-1 function is essential for the proper development of both the endocrine and the exocrine pancreas and for normal metabolic function in the adult. Mutations in the PDX-1 gene are associated with multiple metabolic phenotypes in humans.
MSX1 and Partial Anodontia and the Witkop Syndrome
Authors: Boogaard Marie-Jos H Van Den 
Published: November 2023

Abstract
Msx1, isolated by homology to the Drosophila muscle-segment homeobox (msh) gene, is highly conserved; it plays an important role in inductive epithelial–mesenchymal interactions, leading to vertebrate organogenesis, and is involved in cell differentiation. During embryonic development, Msx1 is intensely expressed in the facial primordium and in a variety of embryonic tissues requiring epithelial– mesenchymal interactions for their morphogenesis, such as limb buds and tooth buds.
MSX2 and ALX4 and Craniosynostosis and Defects of Skull Ossification
Authors: Muller Ulrich 
Published: November 2023

Abstract
Mutations in the homeobox gene MSX2 can result in both craniosynostosis (premature fusion of the calvarial sutures) and its opposite, parietal foramina (PFM) (delayed ossification along the sagittal sutures). The one MSX2 mutation (Pro148His) described in craniosynostosis to date results in a gain of gene function due to increased binding to the consensus MSX binding site and the subsequent overstimulation of MSX2 target genes. Conversely, haploinsufficiency of MSX2 is the cause of PFM. Haploinsufficiency of another homeobox gene, ALX4, can also underlie PFM. No mutation has yet been discovered in this gene in craniosynostosis.
SHOX and Dyschondrosteosis and Turner Syndrome
Authors: Ellison Jay w. 
Published: November 2023

Abstract
The story of the short stature homeobox (SHOX) gene is an example of how observations of different clinical disorders can eventually converge on a single gene. The disorders in this case are dyschondrosteosis, a skeletal dysplasia; Turner syndrome, an aneuploid condition resulting from a missing sex chromosome; and idiopathic short stature (ISS). SHOX is implicated in each of these conditions, although its contribution to the phenotypes varies with respect to both level of involvement and level of experimental proof. The predicted nature of the gene product (as a DNA-binding transcriptional regulator), its abundant expression in bone, and the skeletal phenotypes of patients all point to the placement of SHOX in a developmental pathway of bone development. Details of this pathway are largely unknown, though preliminary studies suggest that SHOX may be important for proper chondrocyte differentiation in the relevant skeletal elements. This notion is supported by observations of a conditional knockout model of a mouse SHOX paralog (Shox2). Functional studies of SHOX have centered on in vitro systems that have identified functional domains of the SHOX gene, messenger RNA (mRNA), and protein. In addition, a cis-regulatory element has been inferred on the basis of deletions in a subset of patients. Continued work on these and other fronts will eventually lead to a better understanding of the role of SHOX in growth and skeletal development.
HLXB9 (MNX1) and Sacral Agenesis and the Currarino Syndrome
Authors: Scherer Stephen , Martucciello Guiseppe , Belloni, Elena , Torre Michele 
Published: November 2023

Abstract
Agenesis of the sacrum is a defect that involves the spinal column, with varying degrees of severity. It is usually sporadic in origin and associated with maternal diabetes. There are also familial forms, such as the Currarino syndrome (CS), in which the defects are transmitted through entire pedigrees, with reduced penetrance in some cases.
Introduction to Paired-Box Genes
Authors: Petrou Petros P , Gruss Peter 
Published: November 2023

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.