bluuebunny/crossref_metadata_2025_split huggingface dataset:
DLL3, MESP2, and LFNG and Spondylocostal Dysostosis
Authors: Turnpenny Peter D , Kusumi, Kenro , Dunwoodie Sally 
Published: November 2023

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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