Signaling Mechanisms, Cellular Adhesion, and More diseases

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Signaling Mechanisms, Cellular Adhesion, and More
diseases

• Genetics

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Signal Transduction

• Occurs on the cell membrane on both side
• Cells n a multicellular organism need to
  communicate with other cells
• In signal transduction molecules on the cell
  membane, assist, transmit,and amplify messages.
• Transduction means to change the signal from the
  environment into a common message understood by
  the cell.

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Signal transduction

• The transduction occurs between a receptor on the
  outside of the cell and a molecule in the
  cytoplasm which will amplify the signal so that
  it is received and acted on

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First messengers

• Messages received by receptors on the outside
• These are the first messengers the signal can
  be light, a chemical gradient,temperature,
  toxins, hormones, or growth factors

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Receptor

• A molecule which is the signal binds to the
  receptor.
• The receptor is attached to a transmembrane
  protein( spans the cell membrane)
• The signal causes a change in the shape or
  conformation of the transmembrane protein

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Cytoplasmic responses

• The membrane affects a regulator molecule that
  then activates an enzyme
• The enzyme causes ATP to form CAMP( cyclic AMP)
• This is a generalized message that can be
  transmitted to the nucleus or to other molecules
  in the cell

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Growth Factor
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NF1
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Effects of Neurofibromatosus
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NF1 and Growth factors

• Chromosome 17
• Neurofibromatosis is an autosomal dominant
  disorder characterized particularly by
  cafe-au-lait spots and fibromatous tumors of the
  skin. Other features are variably present
• Caused by a mutation in the gene for neurofibromin

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NF1 and cancer

• Neurofibromatosis is an autosomal dominant
  disorder characterized particularly by
  cafe-au-lait spots and fibromatous tumors of the
  skin. Other features are variably present

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Protein

• The protein has been called neurofibromin 1 2839
  amino acids
• Expression is tissue and development stage
  specific
• Function GTPase activating protein
• (GAP) interacting with p21RAS - tumor
  suppressor.

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Chromosome 17
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Cellular Adhesion

• Cells touch each other through adhesion
• A precise set of interactions between proteins
  joins the cells in tissues

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Cellular Adhesion

• Inflammation the painful,red swelling at a site
  of injury or infection- illustrates cell adhesion
  
• Inflammation is caused by white blood cells.
  White blood cells flood to injured areas to
  prevent infection
• Cellular adhesion molecules help guide white
  blood cells to the injured area( genetically
  controlled)

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Three Types of CAMS cellular adhesion molecules

• Selectins provide traction by coating the white
  blood cells to slow them
• Blood cells release chemical attractants that
  signal white blood cells to stop this
  activatesCAMs called integrins that latch onto
  white blood cells and CAMs called adhesions
  receptor proteins

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Adhesion receptor

• This extends from the capillary wall at the
  injury site and touches the cytoskeleton beneath
  the capillary lining
• The integin and receptor protein bind the WBC and
  pull in through the membrane to the injury site

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Failure to work

• Creates a disease
• Called leukocyte adhesion deficiency
• A deficiency of CAMS
• The blood does not stop at injured places
• Lack of cell adhesion allows cells to travel
  through the body and metasticize

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Deficiency of CAMs

• Can also lead to arthritic situations where WBC
  attach to a joint when there is not injury

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WBC
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Mechanism
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LAD

• LAD is a rare PI disease, found in one out of
  every million people. This disease causes
  recurrent, life-threatening infections.
  Phagocytes cannot find their way to the site of
  infection to fight off invading germs. LAD is
  autosomal recessive disease, meaning that to be
  born with this disease, both parents must have
  the affected gene.

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Cause

• LAD is caused by a lack of beta 2 integrin, also
  called CD18, molecules. These molecules are
  normally found on the outer surface of
  phagocytes. Without them, the phagocytes cannot
  attach to blood vessel walls and enter infected
  tissues where they help fight infection.
  Mutations in the gene that instructs, or codes
  for, the production of CD18 cause LAD.

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Infections and LAD

• Children with LAD cannot fight off infection
  properly. They may have
• Severe infections of the soft tissue
• Eroding skin sores without pus
• Severe infections of the gums with tooth loss
• Infections of the gastrointestinal tract
• Wounds that heal slowly and may leave scars

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Lesch- Nyhan

• Lesch-Nyhan syndrome (LNS) is a rare, inherited
  disorder caused by a deficiency of the enzyme
  hypoxanthine-guanine phosphoribosyltransferase
  (HPRT). LNS is an X-linked recessive disease--
  the gene is carried by the mother and passed on
  to her son.  LNS is present at birth in baby
  boys. 

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HPRT

• The lack of HPRT causes a build-up of uric acid
  in all body fluids, and leads to symptoms such as
  severe gout, poor muscle control, and moderate
  retardation, which appear in the first year of
  life.  A striking feature of LNS is
  self-mutilating behaviors characterized by lip
  and finger biting that begin in the second year
  of life.

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Uric acid

• Abnormally high uric acid levels can cause sodium
  urate crystals to form in the joints, kidneys,
  central nervous system, and other tissues of the
  body, leading to gout-like swelling in the joints
  and severe kidney problems. 

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Symptoms

• Neurological symptoms include facial grimacing,
  involuntary writhing, and repetitive movements of
  the arms and legs similar to those seen in
  Huntingtons disease.  Because a lack of HPRT
  causes the body to poorly utilize vitamin B12,
  some boys may develop a rare disorder called
  megaloblastic anemia.

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MSUD Maple Syrup Urine Disease

• Maple Syrup Urine Disease (MSUD) or
  branched-chain ketoaciduria is caused by a
  deficiency in activity of the branched-chain
  a-ketoacid dehydrogenase (BCKD) complex (1, 2).
  This metabolic block results in the accumulation
  of the branched-chain amino acids (BCAAs)
  leucine, isoleucine, and valine and the
  corresponding branched-chain alpha-keto acids
  (BCKAs).

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Branched Amino acids
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Characteristics

• MSUD is an autosomal recessive metabolic disorder
  of panethnic distribution. The worldwide
  frequency based on routine screening data from
  26.8 million newborns is approximately one in
  185,000. In the inbred Old Order Mennonite
  population of Lancaster and Lebanon Counties,
  Pennsylvanis, MSUD occurs in approximately one in
  176 newborns.

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Protein

• The human BCKD complex affected in MSUD is a
  macromolecular metabolic machine (molecular mass
  4 x 106 daltons) loosely associated with the
  inner membrane of the mitochondria.

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Affected Pathway
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Dietary recommendations
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MSUD- Synthetic Diet

• The diet centers around a synthetic formula or
  "medical food" which provides nutrients and all
  the amino acids except leucine, isoleucine and
  valine. These three amino acids are added to the
  diet with carefully controlled amounts of food
  to provide the protein necessary for normal
  growth and development without exceeding the
  level of tolerance.
•  

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Wilsons Disease

• Wilson's disease causes the body to retain
  copper. The liver of a person who has Wilson's
  disease does not release copper into bile as it
  should.

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Symptoms

• Wilson's disease is hereditary. Symptoms usually
  appear between the ages of 6 and 20 years, but
  can begin as late as age 40. The most
  characteristic sign is the Kayser-Fleischer
  ringa rusty brown ring around the cornea of the
  eye that can be seen only through an eye exam.

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Liver and Spleen

• Other signs depend on whether the damage occurs
  in the liver, blood, central nervous system,
  urinary system, or musculoskeletal system. Many
  signs can be detected only by a doctor, like
  swelling of the liver and spleen

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Other symptoms

• Some symptoms are more obvious, like jaundice,
  which appears as yellowing of the eyes and skin
  vomiting blood speech and language problems
  tremors in the arms and hands and rigid muscles.

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Treatment

• The disease is treated with lifelong use of
  D-penicillamine or trientine hydrochloride, drugs
  that help remove copper from tissue, or zinc
  acetate, which stops the intestines from
  absorbing copper and promotes copper excretion

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Dietary Restrictions

• Patients will also need to take vitamin B6 and
  follow a low-copper diet, which means avoiding
  mushrooms, nuts, chocolate, dried fruit, liver,
  and shellfish.

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Epidermolysis bullosa

• Epidermolysis bullosa (EB) is a group of
  inherited bullous disorders characterized by
  blister formation in response to mechanical
  trauma. Historically, EB subtypes have been
  classified according to skin morphology.

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Types

• EB is classified into 3 major categories,
  including (1) EB simplex (EBS intraepidermal
  skin separation), (2) junctional EB (JEB skin
  separation in lamina lucida or central BMZ), and
  (3) dystrophic EB (DEB sublamina densa BMZ
  separation see

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Examples
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Biotinidase deficiency

• Biotinidase is a ubiquitous mammalian cell enzyme
  occurring at high levels in the liver, serum, and
  kidney. The primary function is to cleave biotin
  from biocytin, preserving the pool of biotin for
  use as a cofactor for biotin dependent enzymes,
  namely the 4 human carboxylases

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• Disease caused by complete or partial absence of
  the enzyme is associated with a wide spectrum of
  clinical manifestations, including abnormalities
  of the neurological, dermatological,
  immunological, and ophthalmological systems. In
  spite of its rarity, early recognition is crucial
  because expeditious treatment may reverse all of
  its manifestations

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Treatment

• If treated promptly, biotinidase deficiency may
  be asymptomatic. Prolonged symptoms prior to
  institution of biotin therapy may leave the
  patient with varying degrees of neurological
  sequelae, including mental retardation, seizures,
  and coma. Death may result from untreated
  profound biotinidase deficiency.

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Neurological Problems

• Developmental delay
• Ataxia
• Neuropathy
• Auditory nerve dysfunction

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Immunological Problems

• Chronic and possibly lethal fungal infections
  characterize immunological deficiencies.
• Cellular immunity abnormalities are possibly due
  to accumulation of toxic metabolites or biotin
  deficiency itself.
• The immunological dysfunction is ameliorated with
  biotin treatment.