Substrate proteins, destined for elimination, are initially attached to polymers of the highly conserved ubiquitin (Ub) protein. This covalent modification of the substrate targets the conjugated protein to a multicatalytic protease complex, the 26S proteasome. The Ub attachment site in substrate proteins is commonly a Lys side chain. A well-defined series of enzymes orchestrates the attachment of mono- and polyubiquitin to proteins (see figure). Ub is first activated in an ATP-consuming reaction by an E1 Ub-activating enzyme, to which it becomes attached by a high-energy thioester bond. Subsequently, the activated Ub is transferred to the active site Cys of a second protein, an E2 ubiquitin-conjugating enzyme.
With the aid of a third enzyme, called E3 or ubiquitin-protein ligase, E2 catalyses the transfer of (poly)ubiquitin onto the protein that is destined for degradation.
E3 is the most important enzyme in determining the specificity of substrate ubiquitylation.
There are two major classes of mechanistically distinct E3 enzymes, characterized by the
RING (or RING-like) and HECT domains. Both types of E3 enzymes are alike in their ability to establish selective substrate binding. The RING finger uses Cys and His residues to coordinate a pair of zinc ions in a characteristic arrangement (not shown). A smaller set of E3 enzymes contain a domain called the U box, which is a degenerate version of the RINGfinger that achieves the same general fold without coordinating any metal ions. RING and
RING-like E3 enzymes bind to both the E2 enzyme and the substrate, and catalyse the transfer of Ub directly from the E2 enzyme to the substrate. Unlike RING and U-box E3 enzymes, the HECT E3 enzymes have a more direct catalytic role in substrate ubiquitylation.
The activated Ub of the Ub–E2 enzyme thioester is transferred to a conserved Cys residue in the HECT domain of the E3 before finally being transferred to a substrate.
Ubiquitylation is reversed by de-ubiquitylating enzymes (DUBs) that remove ubiquitin from proteins and disassemble polyubiquitin chains. DUBs provide additional regulatory control

before protein degradation, and they are also fundamental for maintaining a sufficient pool of free ubiquitin molecules in the cell.
:دنوشیم داجیا E3 میزنآ درکلمع رد للاتخا هجیتن رد هک ییاه مردنس نیرتمهم
1-Angelman syndrome
Angelman syndrome ( /ˈeɪndʒəlmən/ ; abbreviated AS ) is a neurogenetic disorder characterized by severe intellectual and developmental disability , sleep disturbance, seizures , jerky movements (especially hand-flapping), frequent laughter or smiling, and usually a happy demeanor.
AS is a classic example of genomic imprinting in that it is caused by deletion or inactivation of genes on the maternally inherited chromosome 15 while the paternal copy, which may be of normal sequence, is imprinted and therefore silenced. The sister syndrome, Prader-Willi syndrome , is caused by a similar loss of paternally inherited genes and maternal imprinting.
AS is named after a British pediatrician , Dr. Harry Angelman , who first described the syndrome in 1965. An older, alternative term for AS, "happy puppet syndrome", is generally considered pejorative and stigmatizing so it is no longer the accepted term, though it is sometimes still used as an informal term of diagnosis. People with AS are sometimes known as "angels", both because of the syndrome's name and because of their youthful, happy appearance.
Signs and symptoms
The following text lists signs and symptoms of Angelman syndrome and their relative frequency in affected individuals.
Consistent (100%)
 Developmental delay, functionally severe
 Speech impairment, no or minimal use of words; receptive and non-verbal
 communication skills higher than verbal ones
Movement or balance disorder, usually ataxia of gait and/or tremulous movement of
 limbs
Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span
Frequent (more than 80%)
 Delayed, disproportionate growth in head circumference, usually resulting
 in microcephaly (absolute or relative) by age 2
 Seizures, onset usually < 3 years of age
Abnormal EEG, characteristic pattern with large amplitude slow-spike waves
Associated (20–80%)
 Strabismus
 Hypopigmented skin and eyes

 Tongue thrusting; suck/swallowing disorders
 Hyperactive tendon reflexes


Feeding problems during infancy
 Uplifted, flexed arms during walking
Prominent mandible


Increased sensitivity to heat
 Wide mouth, wide-spaced teeth
Sleep disturbance
 Frequent drooling, protruding tongue


Attraction to/fascination with water
 Excessive chewing/mouthing behaviors
Flat back of head
 Smooth palms
Pathophysiology
Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy , translocation , or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from the mother, the other from the father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sexspecific epigenetic imprinting ; the biochemical mechanism is DNA methylation . In a normal individual, the maternal allele is expressed and the paternal allele is specifically silenced in the developing brain. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome .) It should be noted that the methylation test that is performed for
Angelman syndrome (a defect in UBE3A) is actually looking for methylation on the gene's neighbor SNRPN (which is silenced by methylation on the maternal copy of the gene).
Angelman syndrome can also be the result of mutation of a single gene. This gene ( UBE3A , part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (imprinting). The paternal silencing of the UBE3A gene occurs in a brain region-specific manner; in the hippocampus and cerebellum , the maternal allele is almost exclusively the active one. The most common genetic defect leading to
Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region
15q11-13 causing an absence of UBE3A expression in the paternally imprinted brain regions. UBE3A codes for an E6-AP ubiquitin ligase , which chooses its substrates very selectively, and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying Angelman syndrome in humans.
Initial studies of mice that do not express maternal UBE3A show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning . In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a
-/-
mice.
These results provide links amongst hippocampal synaptic plasticity in vitro , formation of hippocampus-dependent memory in vivo , and the molecular pathology of Angelman syndrome.

Neurophysiology
One of the more notable features of Angelman Syndrome (AS) is the syndrome’s pathognomonic neurophysiological findings. The electroencephalogram (EEG) in
AS is usually very abnormal, and more abnormal than clinically expected. Three distinct interictal patterns are seen in these patients. The most common pattern is a very large amplitude 2–3 Hz rhythm most prominent in prefrontal leads. Next most common is a symmetrical 4–6 Hz high voltage rhythm. The third pattern, 3–6 Hz activity punctuated by spikes and sharp waves in occipital leads, is associated with eye closure. Paroxysms of laughter have no relation to the EEG, ruling out this feature as a gelastic phenomenon.
It appears that the neurons of patients with Angelman syndrome are formed correctly, but they cannot function properly.
Diagnosis
The diagnosis of Angelman syndrome is based on:




 A history of delayed motor milestones and then later a delay in general development,
 especially of speech
Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-legged gait.
Characteristic facial appearance (but not in all cases).
A history of epilepsy and an abnormal EEG tracing.
A happy disposition with frequent laughter
A deletion or inactivity on chromosome 15 by array comparative genomic hybridization (aCGH) or by BACs-on-Beads technology.
Diagnostic criteria for the disorder were initially established in 1995 in collaboration with the
Angelman syndrome Foundation (USA); these criteria have undergone revision in 2005
Treatment
There is currently no cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because AS is usually associated with having multiple varieties of seizures, rather than just the one as in normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman syndrome sleep for a maximum of 5 hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements, and early intervention with physiotherapy is important to encourage joint mobility and prevent stiffening of the joints.
Those with the syndrome are generally happy and contented people who like human contact and play. People with AS exhibit a profound desire for personal interaction with others.
Communication can be difficult at first, but as a child with AS develops, there is a definite character and ability to make themselves understood. People with AS tend to develop strong non-verbal skills to compensate for their limited use of speech. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most afflicted people will not develop more than 5–10 words, if any at all.

Seizures are a consequence, but so is excessive laughter, which is a major hindrance to early diagnosis.
Prognosis
The severity of the symptoms associated with Angelman syndrome varies significantly across the population of those affected. Some speech and a greater degree of self-care are possible among the least profoundly affected. Unfortunately, walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to improve significantly the prognosis (in the areas of cognition and communication) of individuals affected by AS.
Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.
The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent Angelman syndrome girls, but do not seem to affect long-term health.
The facial features remain recognizable with age, but many adults with AS look remarkably youthful for their age.
Puberty and menstruation begin at around the average age. Sexual development is thought to be unaffected, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome.
The majority of those with AS achieve continence by day and some by night. Angelman syndrome is not a degenerative syndrome. Many people with AS improve their living skills with support.
Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults can eat with a knife or spoon and fork, and can learn to perform simple household tasks. General health is fairly good and life-span near average. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis if it is present. The affectionate nature which is also a positive aspect in the younger children may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable.

History
"Boy with a Puppet" or "A child with a drawing" by Giovanni Francesco Caroto
Harry Angelman, a pediatrician working in Warrington , England, first reported three children with this condition in 1965. Angelman later described his choice of the title "Puppet
Children" to describe these cases as being related to an oil painting he had seen while vacationing in Italy:
The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's syndrome is one such story. It was purely by chance that nearly thirty years ago (e.g., circa 1964) three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio Museum in Verona called . . . a Boy with a Puppet. The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group.
Later the name was changed to Angelman syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties.
—Angelman quoted by Charles Williams
Case reports from the United States first began appearing in the medical literature in the early
1980s. In 1987, it was first noted that around half of the children with AS have a small piece of chromosome 15 missing ( chromosome 15q partial deletion )
2-Von Hippel–Lindau (VHL) disease is a rare , autosomal dominant genetic condition that predisposes individuals to benign and malignant tumours. The most common tumours found in VHL are central nervous system and retinal hemangioblastomas , clear cell renal carcinomas , pheochromocytomas , pancreatic neuroendocrine tumours , pancreatic cysts, endolymphatic sac tumors and epididymal papillary cystadenomas.VHL results from a mutation in the von Hippel–Lindau tumor suppressor gene on chromosome 3p25.3.
Epidemiology
VHL disease has an incidence of one in 36,000 births. There is over 90% penetrance by the age of 65.

Slit lamp photograph showing retinal detachment in Von Hippel-Lindau disease.
Signs and symptoms associated with VHL disease include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure.
Conditions associated with VHL disease include angiomatosis , hemangioblastomas , pheochromocytoma , renal cell carcinoma , pancreatic cysts ( pancreatic serous cystadenoma ), endolymphatic sac tumor , and bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women). Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms. Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60-80%. Spinal hemangioblastomas are found in 13-59% of VHL disease and are specific because 80% are found in VHL disease.
Although all of these tumours are common in VHL disease, around half of cases present with only one tumour type.
Genetics
The disease is caused by mutations of the von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found in VHL disease.

Von Hippel–Lindau disease is inherited in an autosomal dominant pattern.
Every cell in the body has 2 copies of every gene. In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours form from only those cells where the second copy of the gene has been mutated. This is known as the two-hit hypothesis . A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop
Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.
30-40% of mutations in the VHL gene consist of 50-250kb deletion mutations that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-
70% of VHL disease is caused by the truncation of pVHL by nonsense mutations , indel mutations or splice site mutations .
VHL disease subtypes
VHL disease can be subdivided according to the clinical manifestations, although these groups often correlate with certain types of mutations present in the VHL gene.
Type 1

Type one often has deletion or nonsense mutations . This group manifests mostly as hemangioblastomas whereas clear-cell renal carcinomas and pheochromocytomas are rare.PELIK2 SAHAJA [
Type 2
Type 2 VHL disease is subdivided into Type 2A, B and C which are characterised mostly by missense mutations . Type 2A is at risk of hemangioblastomas and pheochromocytomas, but not clear-cell renal carcinomas. Type 2B is at risk of all three tumours, with a higher risk of clear-cell renal carcinoma. Type 2C is at risk for only pheochromocytoma.
Type 3
Type 3 VHL disease has a risk of Chuvash polycythaemia .
VHL protein
The regulation of HIF1α by pVHL. Under normal oxygen levels, HIF1α binds pVHL through
2 hydroxylated proline residues and is polyubiquitinated by pVHL. This leads to its degradation via the proteasome. During hypoxia, the proline residues are not hydroxylated and pVHL cannot bind. HIF1α causes the transcription of genes that contain the hypoxia response element. In VHL disease, genetic mutations cause alterations to the pVHL protein, usually to the HIF1α binding site.
The VHL protein (pVHL) is involved in the regulation of a protein known as hypoxia inducible factor 1α
(HIF1α). This is a subunit of a heterodimerictranscription factor that at normal cellular oxygen levels is highly regulated. In normal physiological conditions, pVHL recognises and binds to HIF1α only when oxygen is present due to the post translational hydroxylation of 2 proline residues within the HIF1α protein. pVHL is an E3 ligase that ubiquitinates HIF1α and causes its degradation by the proteasome . In low oxygen conditions or in cases of VHL disease where the VHL gene is mutated, pVHL does not bind to HIF1α. This allows the subunit to dimerise with HIF1β and activate the transcription of a number of genes, including vascular endothelial growth factor , platelet-derived growth factor
B , erythropoietin and genes involved in glucose upatake and metabolism.
Diagnosis
The detection of tumours specific to VHL disease is important in the disease's diagnosis. In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis. As all the tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history.

Genetic diagnosis is also useful in VHL disease diagnosis. In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations. These tests can be used to screen family members of those afflicted with
VHL disease; de novo cases that produce genetic mosaicism are more difficult to detect because mutations are not found in the white blood cells that are used for genetic analysis.
Treatmen
There is no current way to reverse the presence of the VHL mutation in patients. Nonetheless, early recognition and treatment of specific manifestations of VHL disease can substantially decrease complications and improve quality of life. For this reason, individuals with VHL disease are usually screened routinely for retinal angiomas, CNS hemangioblastomas, clearcell renal carcinomas and pheochromocytomas. CNS hemangioblastomas are usually surgically removed if they are symptomatic. Photocoagulation and cryotherapy are usually used for the treatment of symptomatic retinal angiomas, although anti-angiogenic treatments may also be an option. Renal tumours may be removed by a partial nephrectomy or other techniques such as radiofrequency ablation .
History
Original von Hippel's description of disease.
The German ophthalmologist Eugen von Hippel first described angiomas in the eye in 1904.
Arvid Lindau described the angiomas of the cerebellum and spine in 1927. The term von
Hippel-Lindau disease was first used in 1936, however its use became common only in the
1970s.
یعازخ،یلباز،یتارب،یدمحا