Transcript Kawasaki Disease - Harlem Children Society

Familial Hypercholesterolemia
By: Kasarah Allen
City College of New York
Frederick Douglass Academy
Abstract
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Patients suffering from familial hypercholesterolemia have a much more serious
condition than those people who have high levels of cholesterol. These FH patients
have a much higher chance of suffering from heart attacks and stroke.
Hypercholesterolemia describes the people with high levels of cholesterol. In other
words, the people who have too much cholesterol circulating in their bloodstream. It is
known to be caused by the consumption of a high-cholesterol diet and/or the genetic
disease familial hypercholesterolemia (FH). Human body usually produces about twothirds of its needed cholesterol in the liver, thus very little supplement of cholesterol is
required. The homozygous FH is more rare, occuring with the frequency of about 1 in
a million. The statistics for the homozygous FH is not surprising though, since patients
suffering from two alleles of this gene usually do not survive pass their teens. The
condition of hypercholesterolemia in FH patients are detectable at birth or shortly
thereafter. The cholesterol levels in heterozygous patients are between350 to 500
mg/dL, and in homozygous, the levels are between 700 to 1,200 mg/dL.
Hypercholesterolemia is a silent disease. No symptoms will occur until the resulting
chest pain of a heart attack or the symptoms of a stoke. Tendon xanthomas commonly
occur in FH patients. The heterozygous will develop these later in life, but the
homozygous usually develops them in their childhood. Xanthomas are lesions caused
by cholesterol deposits in various parts of the body. The common places are in the
extensor tendons of the hands and eyelids (know as xanthelasmas).
Introduction
• Familial hypercholesterolemia (FH) is a genetic
disease in which patients have greatly elevated
levels of serum cholesterol and suffer from heart
attacks early in life.
• Although moderate hypercholesterolemia is a
common finding in industrialized countries,
heterozygous FH occurs in approximately 1 per
500 persons worldwide.
• FH is a disorder of absent or grossly
malfunctioning low-density lipoprotein (LDL)
receptors.
Background
• In 1972, Michael S. Brown and Joseph L.
Goldstein hypothesized that surmised that
cholesterol overproduction results from defect in
the control mechanisms that normally regulate
cholesterol biosynthesis.
• In 1974, Brown and Goldstein demonstrated that
the lesion in FH cells is a defect in LDL binding
to a receptor on the surface.
LDLR
PDB code: 1N7D
• The low-density lipoprotein
receptor mediates
cholesterol homeostasis
through endocytosis of
lipoproteins.
• Mutations in this gene cause
the autosomal dominant
disorder, familial
hypercholesterolemia.
• The LDL receptor gene is
located on the short arm of
chromosome 19, and the
protein is composed of 860
amino acids.
The importance of the LDL
Receptor
• The addition of LDL to the normal human
fibroblasts inhibits the activity of 3-hydroxy-3
methylglutaryl coenzyme A reductase (HMG-Co
A reductase), the rate-limiting enzyme in the
cholesterol biosynthetic pathway.
• HMG-Co A reductase activity is unaffected by
addition to LDL to the cells of FH patients,
resulting in over production of cholesterol by FH
cells.
The importance of the LDL
Receptor cont’d
• Goldstein and Brown discovered the LDL
receptor and determined that FH was
caused by an autosomal dominant
mutation. Since then, more than 700
mutations have been identified that have a
meaningful impact on receptor function.
LDL receptor function ranges from
completely absent to approximately 25%
of normal receptor activity.
Comparison
• Comparison between humans and pacific oysters using
FASTA
• >gi|28373937|pdb|1N7D|A Chain A, Extra cellular
Domain Of The Ldl Receptor Length=699 Score = 51.6
bits (122), Expect = 6e-05, Method: Composition-based
stats. Identities = 32/70 (45%), Positives = 32/70 (45%),
Gaps = 0/70 (0%) Query 287
DIQAPXGLAVXXIXSNIYXXXXVLXXXXXXXXXX
XXXXXXXXXXXXXXXXIVVXPVHGFM 346
DIQAP GLAV I SNIY VL IVV PVHGFM Sbjct 451
DIQAPDGLAVDWIHSNIYWTDSVLGTVSVADTKGV
KRKTLFREQGSKPRAIVVDPVHGFM 510 Query 347
YXTXXGTPAK 356 Y T GTPAK Sbjct 511
YWTDWGTPAK 520
Protein Modeling
• MOE is used for homology or comparative
modeling of protein three-dimensional structures.
• The user provides an alignment of a sequence to
be modeled with known related structures and
MOE automatically calculates a model
containing all non-hydrogen atoms.
• MOE implements comparative protein structure
modeling by satisfaction of spatial restraints, and
can perform many additional tasks
Structure Prediction
• This structure was
created by Moe. It’s
the template for the
LDLR protein.
• This is what the
LDLR protein would
look like based on
similar protein of the
same gene.
Space Filling Model
•Space filling molecular
models show the relative
atomic sizes of the atoms of
the molecule.
•This model shows the
carbons (gray), hydrogen's
(light gray), oxygen (blue),
carbon monoxide's (red), and
sulfur (yellow) of the protein.
Ramachandran Plot
• Ramachandran Plot shows alpha helixes and beta
sheets.
Further Studies
• Curing homozygous patients is very difficult because they
express little or no activity from the LDL receptor. They
are resistant to most cholesterol-lowering drugs. Liver
transplantation can provide the missing LDL receptors
but requires special long-term follow-up cares for the
transplanted organs, including continuous
immunosuppressants. FH homozygous are currently
treated with modified forms of plasmapheresis that
selectively remove very small density lipoprotein and
low-density lipoproteins from the plasma. Also, the
modern approach to this problem is gene therapy.
Further Studies Continued
• Knowing the structure of the LDL receptor
scientists can better understand the effects
it has on Familial Hypercholesterolemia
patients.
• For example, scientist can find why the
LDL receptor fails to activate and bind to
the surface and can learn how to provide
LDL receptors to FH patients.
References
• The Cell: A Molecular Approach
Copyright © 2000 by Geoffrey M. Cooper
• http://www.ncbi.nlm.nih.gov/
• http://www.pdb.org/
• http://dwb.unl.edu/Teacher/NSF/C10/C10L
inks/www.middlebury.edu/~ch0337/ho/fh.h
tml
• MOE
Acknowledgements
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Dr. Y. Gosser
Karin Yemul
Annie He
City College of New york
Harlem Children Society
MSKCC