Alagille Syndrome
Receptor, Notch2
Chromosomes, Human, Pair 20
Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
Facies
Receptors, Notch
Cholestasis
Membrane Proteins
Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. (1/67)
In vertebrates, the hedgehog family of cell signaling proteins and associated downstream network components play an essential role in mediating tissue interactions during development and organogenesis. Loss-of-function or misexpression mutation of hedgehog network components can cause birth defects, skin cancer and other tumors. The mammary gland is a specialized skin derivative requiring epithelial-epithelial and epithelial-stromal tissue interactions similar to those required for development of other organs, where these interactions are often controlled by hedgehog signaling. We have investigated the role of the Patched-1 (Ptc1) hedgehog receptor gene in mammary development and neoplasia. Haploinsufficiency at the Ptc1 locus results in severe histological defects in ductal structure, and minor morphological changes in terminal end buds in heterozygous postpubescent virgin animals. Defects are mainly ductal hyperplasias and dysplasias characterized by multilayered ductal walls and dissociated cells impacting ductal lumens. This phenotype is 100% penetrant. Remarkably, defects are reverted during late pregnancy and lactation but return upon involution and gland remodeling. Whole mammary gland transplants into athymic mice demonstrates that the observed dysplasias reflect an intrisic developmental defect within the gland. However, Ptc1-induced epithelial dysplasias are not stable upon transplantation into a wild-type epithelium-free fat pad, suggesting stromal (or epithelial and stromal) function of Ptc1. Mammary expression of Ptc1 mRNA is both epithelial and stromal and is developmentally regulated. Phenotypic reversion correlates with developmentally regulated and enhanced expression of Indian hedgehog (Ihh) during pregnancy and lactation. Data demonstrate a critical mammary role for at least one component of the hedgehog signaling network and suggest that Ihh is the primary hedgehog gene active in the gland. (+info)The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome. (2/67)
The establishment of the cardiovascular system represents an early, critical event essential for normal embryonic development, and defects in cardiovascular development are a frequent cause of both in utero and neonatal demise. Congenital cardio-vascular malformations, the most frequent birth defect, can occur as isolated events, but are frequently presented clinically within the context of a constellation of defects that involve multiple organs and that define a specific syndrome. In addition, defects can be a primary effect of gene mutations or result from secondary effects of altered cardiac physiology. Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the heart, liver, eye, skeleton and kidney. Congenital heart defects, the majority of which affect the right-sided or pulmonary circulation, contribute significantly to mortality in AGS patients. Recently, mutations in Jagged1 ( JAG1 ), a conserved gene of the Notch intercellular signaling pathway, have been found to cause AGS. In order to begin to delineate the role of JAG1 in normal heart development we have studied the expression pattern of JAG1 in both the murine and human embryonic heart and vascular system. Here, we demonstrate that JAG1 is expressed in the developing heart and multiple associated vascular structures in a pattern that correlates with the congenital cardiovascular defects observed in AGS. These data are consistent with an important role for JAG1 and Notch signaling in early mammalian cardiac development. (+info)Living related donor liver transplantation in a patient with severe aortic stenosis. (3/67)
We report the successful anaesthetic management of a young girl with Alagille's syndrome and severe aortic stenosis (resting pressure gradient 88 mm Hg) undergoing living related donor liver transplantation (LRDLT). The patient had end-stage liver disease and LRDLT was performed before replacement of the aortic valve. Anaesthesia was conducted uneventfully with the aid of a pulmonary artery catheter. Intra-aortic balloon pumping was used in the perioperative period for protection against myocardial ischaemia. Total clamping of the inferior vena cava was avoided during surgery and volume administration was guided by the pulmonary artery pressure. A stable circulation was maintained in the reperfusion period. The patient was discharged from hospital on day 54 after operation with normal liver function. Two years later her aortic valve was replaced successfully. (+info)JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype. (4/67)
Alagille syndrome (AGS, MIM 118450) is an autosomal dominant disorder with a variable phenotype characterised by hepatic, eye, cardiac, and skeletal malformations and a characteristic facial appearance. Mutations within the gene JAGGED1 (JAG1), which encodes a ligand for NOTCH receptor(s), has been shown to cause Alagille syndrome. Interactions of NOTCH receptors and their ligands influence cell fate decisions in several developmental pathways. We report the tissue expression of JAG1 in human embryos. We have performed tissue in situ hybridisation on human embryos aged 32-52 days using (35)S labelled riboprobes for JAG1. JAG1 is expressed in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube. We conclude that JAG1 is expressed in the structures affected in Alagille syndrome, such as the pulmonary artery, anterior chamber of the eye, and face. (+info)Does liver transplantation affect growth pattern in Alagille syndrome? (5/67)
Alagille syndrome (AGS) is frequently associated with growth failure, which has been attributed to concurrent congenital anomalies, cholestasis, and malabsorption and/or malnutrition. However, the underlying cause of the growth failure is not well understood. Our objective is to analyze the growth pattern in 26 patients with AGS and the possible effect that orthotopic liver transplantation (OLT) may have on this pattern. The standardized height, weight, and growth velocity of 26 pair-matched patients with AGS were compared. Thirteen patients underwent OLT. Repeated-measure ANOVA methods were used for the statistical analysis. The overall mean standardized height (z score) was -2.92 in the OLT group versus -1.88 in the non-OLT group (P =.03). The overall mean standardized weight was -1. 21 in the non-OLT group and -1.67 in the OLT group (P =.23). In 15 patients, birth weight was 2.82 +/- 0.4 kg, for a mean standardized weight of -0.95, and weight at diagnosis was 4.53 +/- 2.12 kg, for a mean standardized weight of -1.56. Bone age was delayed in the 9 patients who underwent bone-age analysis. Growth hormone therapy administered to 2 patients did not improve growth. Patients with AGS had growth failure secondary to other factors in addition to liver disease. Growth failure beginning in the prenatal period supports a genetic basis for this feature. Growth improvement up to normal levels should not be expected as a benefit of OLT in these patients. Growth failure as a primary indication for OLT should be cautiously examined in patients with AGS. (+info)Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome. (6/67)
Jagged1 (JAG1) is a cell surface ligand in the Notch signaling pathway and mutations in this gene cause Alagille syndrome (AGS). JAG1 mutations have been identified in 60-70% of AGS patients studied, and these include total gene deletions ( approximately 6%), protein-truncating mutations (insertions, deletions and nonsense mutations) (82%) and missense mutations (12%). Based on the finding that total JAG1 deletions cause AGS, haploinsufficiency has been hypothesized to be a mechanism for disease causation; however, the mechanism by which missense mutations cause disease is not understood. To date, 25 unique missense mutations have been observed in AGS patients. Missense mutations are non-randomly distributed across the protein with clusters at the 5' end of the protein, in the conserved DSL domain, and two clusters within the EGF repeats. To understand the effect of the missense mutations on protein localization and function, we have studied four missense mutations (R184H, L37S, P163L and P871R). In two assays of JAG1 function, R184H and L37S are associated with loss of Notch signaling activity relative to wild-type JAG1. Neither R184H or L37S is present on the cell surface and both are abnormally glycosylated. Furthermore, these mutations lead to abnormal accumulation of the protein, possibly in the endoplasmic reticulum. Both P163L and P871R are associated with normal levels of Notch signaling activity and are present on the cell surface, consistent with these changes being polymorphisms rather than disease-causing mutations. (+info)Parental mosaicism of JAG1 mutations in families with Alagille syndrome. (7/67)
The Alagille syndrome (AGS), a congenital disorder affecting liver, heart, skeleton and eye in association with a typical face, is an autosomal dominant disease with nearly complete penetrance and variable expression. AGS is caused by mutations in the developmentally important JAG1 gene. In our mutation screening, where 61 mutations in JAG1 were detected, we identified five cases where mosaicism is present. Our results point to a significant frequency of mosaicism for JAG1 mutations in AGS of more than 8.2%. Because mosaicism may be associated with a very mild phenotype, the appropriate diagnosis of AGS and consequently the determination of the recurrence risk can be complicated. (+info)Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. (8/67)
BACKGROUND AND AIMS: Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS). PATIENTS AND METHODS: We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit. RESULTS: At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%, respectively. Neonatal cholestatic jaundice was associated with poorer survival with native liver (p=0.0004). CONCLUSIONS: The prognosis of liver disease in AGS is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease, demanding follow up throughout life. (+info)Alagille syndrome is a genetic disorder that affects the liver, heart, and other parts of the body. It is also known as Arteriohepatic dysplasia or Alagille-Watson syndrome. The main features of this condition include:
1. Liver disease: Most individuals with Alagille syndrome have a liver disorder called bile duct paucity, which means that the small tubes (bile ducts) inside the liver that carry bile to the intestine are narrowed or missing. This can lead to liver scarring and damage over time.
2. Heart defects: About 90% of people with Alagille syndrome have a congenital heart defect, such as pulmonary stenosis (narrowing of the pulmonary valve) or tetralogy of Fallot (a combination of four heart defects).
3. Skeletal abnormalities: Many individuals with Alagille syndrome have distinctive facial features and skeletal changes, such as a broad forehead, wide-set eyes, a pointed chin, and butterfly-shaped vertebrae in the spine.
4. Eye problems: Approximately 90% of people with Alagille syndrome have eye abnormalities, including posterior embryotoxon (a narrowing of the drainage angle of the eye) or retinal changes.
5. Kidney issues: Up to 40% of individuals with Alagille syndrome may experience kidney problems, such as renal dysplasia (abnormal kidney development) or vesicoureteral reflux (backflow of urine from the bladder into the ureters).
6. Other features: Some people with Alagille syndrome may have growth delays, cognitive impairment, or hearing loss.
Alagille syndrome is caused by mutations in one of two genes: JAG1 or NOTCH2. These genes play crucial roles in embryonic development and tissue growth. Inheritance of Alagille syndrome is autosomal dominant, meaning that a person has a 50% chance of inheriting the condition if one parent carries the mutated gene. However, about 30-40% of cases result from new (de novo) mutations and have no family history of the disorder.
Notch2 is a type of receptor that belongs to the Notch family of single-pass transmembrane proteins. The Notch signaling pathway plays critical roles in various developmental processes, including cell fate determination, differentiation, proliferation, and apoptosis.
The Notch2 receptor is composed of several domains, including an extracellular domain containing multiple epidermal growth factor-like repeats, a transmembrane domain, and an intracellular domain. The extracellular domain of the Notch2 receptor interacts with its ligands, which are expressed on the surface of neighboring cells. This interaction triggers a series of proteolytic cleavage events that release the intracellular domain of the Notch2 receptor into the cytoplasm.
The intracellular domain of the Notch2 receptor then translocates to the nucleus, where it interacts with the DNA-binding protein CSL (CBF1/RBPJkappa in humans) and other cofactors to regulate gene transcription. Dysregulation of the Notch2 signaling pathway has been implicated in various human diseases, including cancer, cardiovascular disease, and neurological disorders.
Human chromosome pair 20 is one of the 23 pairs of human chromosomes present in every cell of the body, except for the sperm and egg cells which contain only 23 individual chromosomes. Chromosomes are thread-like structures that carry genetic information in the form of genes.
Human chromosome pair 20 is an acrocentric chromosome, meaning it has a short arm (p arm) and a long arm (q arm), with the centromere located near the junction of the two arms. The short arm of chromosome 20 is very small and contains few genes, while the long arm contains several hundred genes that play important roles in various biological processes.
Chromosome pair 20 is associated with several genetic disorders, including DiGeorge syndrome, which is caused by a deletion of a portion of the long arm of chromosome 20. This syndrome is characterized by birth defects affecting the heart, face, and immune system. Other conditions associated with abnormalities of chromosome pair 20 include some forms of intellectual disability, autism spectrum disorder, and cancer.
Calcium-binding proteins (CaBPs) are a diverse group of proteins that have the ability to bind calcium ions (Ca^2+^) with high affinity and specificity. They play crucial roles in various cellular processes, including signal transduction, muscle contraction, neurotransmitter release, and protection against oxidative stress.
The binding of calcium ions to these proteins induces conformational changes that can either activate or inhibit their functions. Some well-known CaBPs include calmodulin, troponin C, S100 proteins, and parvalbumins. These proteins are essential for maintaining calcium homeostasis within cells and for mediating the effects of calcium as a second messenger in various cellular signaling pathways.
Intercellular signaling peptides and proteins are molecules that mediate communication and interaction between different cells in living organisms. They play crucial roles in various biological processes, including cell growth, differentiation, migration, and apoptosis (programmed cell death). These signals can be released into the extracellular space, where they bind to specific receptors on the target cell's surface, triggering intracellular signaling cascades that ultimately lead to a response.
Peptides are short chains of amino acids, while proteins are larger molecules made up of one or more polypeptide chains. Both can function as intercellular signaling molecules by acting as ligands for cell surface receptors or by being cleaved from larger precursor proteins and released into the extracellular space. Examples of intercellular signaling peptides and proteins include growth factors, cytokines, chemokines, hormones, neurotransmitters, and their respective receptors.
These molecules contribute to maintaining homeostasis within an organism by coordinating cellular activities across tissues and organs. Dysregulation of intercellular signaling pathways has been implicated in various diseases, such as cancer, autoimmune disorders, and neurodegenerative conditions. Therefore, understanding the mechanisms underlying intercellular signaling is essential for developing targeted therapies to treat these disorders.
"Facies" is a medical term that refers to the typical appearance of a person or part of the body, particularly the face, which may provide clues about their underlying medical condition or genetic background. A specific facies is often associated with certain syndromes or disorders. For example, a "downsyndrome facies" refers to the distinctive facial features commonly found in individuals with Down syndrome, such as a flattened nasal bridge, almond-shaped eyes, and an upward slant to the eyelids.
It's important to note that while facies can provide valuable diagnostic information, it should be used in conjunction with other clinical findings and genetic testing to make a definitive diagnosis. Additionally, facies should be described objectively and without judgment, as they are simply physical characteristics associated with certain medical conditions.
Notch receptors are a type of transmembrane receptor proteins that play crucial roles in cell-cell communication and regulation of various biological processes, including cell fate determination, differentiation, proliferation, and apoptosis. These receptors are highly conserved across species and are essential for normal development and tissue homeostasis.
The Notch signaling pathway is initiated when the extracellular domain of a Notch receptor on one cell interacts with its ligand (such as Delta or Jagged) on an adjacent cell. This interaction triggers a series of proteolytic cleavage events that release the intracellular domain of the Notch receptor, which then translocates to the nucleus and regulates gene expression by interacting with transcription factors like CSL (CBF1/RBP-Jκ/Su(H)/Lag-1).
There are four known Notch receptors in humans (Notch1-4) that share a similar structure, consisting of an extracellular domain containing multiple epidermal growth factor (EGF)-like repeats, a transmembrane domain, and an intracellular domain. Mutations or dysregulation of the Notch signaling pathway have been implicated in various human diseases, including cancer, cardiovascular disorders, and developmental abnormalities.
A syndrome, in medical terms, is a set of symptoms that collectively indicate or characterize a disease, disorder, or underlying pathological process. It's essentially a collection of signs and/or symptoms that frequently occur together and can suggest a particular cause or condition, even though the exact physiological mechanisms might not be fully understood.
For example, Down syndrome is characterized by specific physical features, cognitive delays, and other developmental issues resulting from an extra copy of chromosome 21. Similarly, metabolic syndromes like diabetes mellitus type 2 involve a group of risk factors such as obesity, high blood pressure, high blood sugar, and abnormal cholesterol or triglyceride levels that collectively increase the risk of heart disease, stroke, and diabetes.
It's important to note that a syndrome is not a specific diagnosis; rather, it's a pattern of symptoms that can help guide further diagnostic evaluation and management.
Cholestasis is a medical condition characterized by the interruption or reduction of bile flow from the liver to the small intestine. Bile is a digestive fluid produced by the liver that helps in the breakdown and absorption of fats. When the flow of bile is blocked or reduced, it can lead to an accumulation of bile components, such as bilirubin, in the blood, which can cause jaundice, itching, and other symptoms.
Cholestasis can be caused by various factors, including liver diseases (such as hepatitis, cirrhosis, or cancer), gallstones, alcohol abuse, certain medications, pregnancy, and genetic disorders. Depending on the underlying cause, cholestasis may be acute or chronic, and it can range from mild to severe in its symptoms and consequences. Treatment for cholestasis typically involves addressing the underlying cause and managing the symptoms with supportive care.
Membrane proteins are a type of protein that are embedded in the lipid bilayer of biological membranes, such as the plasma membrane of cells or the inner membrane of mitochondria. These proteins play crucial roles in various cellular processes, including:
1. Cell-cell recognition and signaling
2. Transport of molecules across the membrane (selective permeability)
3. Enzymatic reactions at the membrane surface
4. Energy transduction and conversion
5. Mechanosensation and signal transduction
Membrane proteins can be classified into two main categories: integral membrane proteins, which are permanently associated with the lipid bilayer, and peripheral membrane proteins, which are temporarily or loosely attached to the membrane surface. Integral membrane proteins can further be divided into three subcategories based on their topology:
1. Transmembrane proteins, which span the entire width of the lipid bilayer with one or more alpha-helices or beta-barrels.
2. Lipid-anchored proteins, which are covalently attached to lipids in the membrane via a glycosylphosphatidylinositol (GPI) anchor or other lipid modifications.
3. Monotopic proteins, which are partially embedded in the membrane and have one or more domains exposed to either side of the bilayer.
Membrane proteins are essential for maintaining cellular homeostasis and are targets for various therapeutic interventions, including drug development and gene therapy. However, their structural complexity and hydrophobicity make them challenging to study using traditional biochemical methods, requiring specialized techniques such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and single-particle cryo-electron microscopy (cryo-EM).
Bile ducts are tubular structures that carry bile from the liver to the gallbladder for storage or directly to the small intestine to aid in digestion. There are two types of bile ducts: intrahepatic and extrahepatic. Intrahepatic bile ducts are located within the liver and drain bile from liver cells, while extrahepatic bile ducts are outside the liver and include the common hepatic duct, cystic duct, and common bile duct. These ducts can become obstructed or inflamed, leading to various medical conditions such as cholestasis, cholecystitis, and gallstones.
Alagille syndrome - Wikipedia
Alagille syndrome: MedlinePlus Genetics
Pediatric Alagille Syndrome
Alagille Syndrome: Practice Essentials, Pathophysiology, Etiology
Alagille syndrome - American Kidney Fund (AKF)
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