Transcript Familial Hypercholesterolemia

Familial
Hypercholesterolemia
Honors Genetics
2006
Gel Interpretation
 Measure
the distance from the
well to the bands( DNA
fragments in the marker)
 Graph using the marker sizes
for Lambda Hind III
 Interpolate the sizes of the
bands for the patients, Normal
and FHC control to verify your
visual observations and
impressions
Hypercholesterolemia Gel
Results
N
FH
C
1
2
3
marke
r
Gel Interpreation
 Patient
1 – Homozygous
recessive – both copies of the
normal LDLR receptor
 Patient 2 – Heterozygous for
the LDLR receeptor
 Patient 3- Homozygous dominant
for the LDLR receptor – The
most severe form of the disease
What is cholesterol??

Cholesterol is one of the body's fats
(lipids). Cholesterol and another lipid,
triglyceride, are important building
blocks in the structure of cells and
are also used in making hormones and
producing energy.
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To some extent, the cholesterol level
in blood depends on what you eat but
it is mainly dependent on how the
body makes cholesterol in the liver.
Cholesterol and the
Steroid Rings
Desirable cholesterol
levels
Desirable — Less than 200 mg/dL
Borderline high risk — 200–239
mg/dL
High risk — 240 mg/dL and over
 If your total cholesterol is less than
200 mg/dL, your heart attack risk is
relatively low, unless you have other
risk factors. Even with a low risk,
it's still smart to eat foods low in
saturated fat and cholesterol, and
also get plenty of physical activity.
Have your cholesterol levels
measured every five years — or more
often if you're a man over 45 or a
woman over 55
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Low density lipoproteins
This is sometimes called “ bad “
cholesterol
 the blood, and the cholesterol from
LDL is the main source of damaging
buildup and blockage in the arteries.
 Thus, the more LDL-cholesterol you
have in your blood, the greater your
risk of heart disease. If you have
heart disease or are at high risk for
developing it and your LDL is 100
mg/dLor higher, your cholesterol
may well be too high for you.
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High Density
Lipoproteins
HDL carry cholesterol in the blood
from other parts of the body back
to the liver, which leads to its
removal from the body.
 So HDL help keep cholesterol from
building up in the walls of the
arteries. If your level of HDLcholesterol is below 40 mg/dL, you
are at substantially higher risk for
heart disease.
 The higher your HDL-cholesterol,
the better. The average HDLcholesterol for men is about 45
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Tests in the Lipid Profile
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Total Cholesterol
HDL Cholesterol
LDL Cholesterol
VLDL Cholesterol
Triglycerides
Apolipoprotein A1Extended Lipid
Profile.
Apolipoprotein B
Lipoprotein(a)
 Before
withdrawing blood for
lipid profile :
a. 12 - 14 hours fasting
sample is required.
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b. Individuals should have
been on their usual diet.
Case History
referene - OMIM
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European populations.
Like the French Canadians, the South Afrikaners
appear to have a unique form of mutation in the
LDLR gene consistent with founder effect (Brink et
al., 1987). Because of the presumed role of founder
effect on the high frequency of familial
hypercholesterolemia in South Africa, it is not
surprising that Kotze et al. (1987) found a
predominance of 2 haplotypes in 27 informative
families with FH. In a study of homozygotes from
the Afrikaner population in South Africa,
Leitersdorf et al. (1989) found that 2 mutations
account for more than 95% of the mutant LDL
receptor genes. Both mutations were basepair
substitutions that resulted in a single amino acid
change and both could be detected readily with PCR
and restriction analysis. The findings were
considered consistent with the high frequency of
FH being due to founder effect.
Chromosome – 19.13.2
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Start:
11,061,132 bp
from pterEnd:
11,105,490 bp
from pterSize:
44,358 bases
Gene Expression
SNP – Single nucleotide
polymorphism
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CTATGACACCA/GTCATCAGCAG
rs11669576
F11083300(+)CCACACGAAGA/GCCTGCAAGGC rs5928
F11101240(+)AAGAACTGGCA/GGCTTAAGAAC 1R/Q ns 2A:0.01MN 310 -rs5930
F,C,A11085265(+)TCATCAGCAGA/GGACATCCAGG 1R/R syn 3A:0.37MN
EA 1810 -rs5927
F,C,A11094941(+)CAACCACCCGA/GCCTGTTCCCG 1R/R syn 2A:0.08MN EA
1620
rs5925
F,C,A11091881(+)AGGATATGGTC/TCTCTTCCACA 1V/V syn 3C:0.18MN EA
1810 -rs688
F,C,A11088602(+)TCGATGTCAAC/TGGGGGCAACC 1N/N syn 1T:0.32MN
126
rs5929
F,C11087800(+)GGGGAACTCCC/TGCCAAGATCA 1P/P syn 2T:0.04MN 310
rs1799898
F,C11088554(+)GTGGCCGCCTC/TTACTGGGTTG 1L/L syn 0-------rs5933
F,C11085090(+)GCAATAGAATC/TTACTGGTCTG
HGMD
 http://archive.uwcm.ac.uk/uwcm
/mg/search/119362.html
 This data base shows all the
different mutations
 For Familial
hypercholesterolemia there are
806 mutations
 457 mutations are missense and
nonsense
Substitution mutations
 GGG-AGG
Gly-Arg
Hypercholesterolaemia
 GCG-GAG Ala-Glu
Hypercholesterolaemia
 CTC-CCC Leu-Pro
Hypercholesterolaemia
 cGAG-TAG Glu-Term
Hypercholesterolaemia
RCSB – The LDLR
receptor
Sequence for LDLR
protein
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10 20 30 40 50 60 MGPWGWKLRW TVALLLAAAG TAVGDRCERN
EFQCQDGKCI SYKWVCDGSA ECQDGSDESQ 70 80 90 100 110
120 ETCLSVTCKS GDFSCGGRVN RCIPQFWRCD GQVDCDNGSD
EQGCPPKTCS QDEFRCHDGK 130 140 150 160 170 180
CISRQFVCDS DRDCLDGSDE ASCPVLTCGP ASFQCNSSTC
IPQLWACDND PDCEDGSDEW 190 200 210 220 230 240
PQRCRGLYVF QGDSSPCSAF EFHCLSGECI HSSWRCDGGP
DCKDKSDEEN CAVATCRPDE 250 260 270 280 290 300
FQCSDGNCIH GSRQCDREYD CKDMSDEVGC VNVTLCEGPN
KFKCHSGECI TLDKVCNMAR 310 320 330 340 350 360
DCRDWSDEPI KECGTNECLD NNGGCSHVCN DLKIGYECLC
PDGFQLVAQR RCEDIDECQD 370 380 390 400 410 420
PDTCSQLCVN LEGGYKCQCE EGFQLDPHTK ACKAVGSIAY
LFFTNRHEVR KMTLDRSEYT 430 440 450 460 470 480
SLIPNLRNVV ALDTEVASNR IYWSDLSQRM ICSTQLDRAH
GVSSYDTVIS RDIQAPDGLA 490 500 510 520 530 540
VDWIHSNIYW TDSVLGTVSV ADTKGVKRKT LFRENGSKPR
AIVVDPVHGF MYWTDWGTPA 550 560 570 580 590 600
KIKKGGLNGV DIYSLVTENI QWPNGITLDL LSGRLYWVDS
KLHSISSIDV NGGNRKTILE 610 620 630 640 650 660
DEKRLAHPFS LAVFEDKVFW TDIINEAIFS ANRLTGSDVN
LLAENLLSPE DMVLFHNLTQ 670 680 690 700 710 720
PRGVNWCERT TLSNGGCQYL CLPAPQINPH SPKFTCACPD
GMLLARDMRS CLTEAEAAVA 730 740 750 760 770 780
TQETSTVRLK VSSTAVRTQH TTTRPVPDTS RLPGATPGLT
TVEIVTMSHQ ALGDVAGRGN 790 800 810 820 830 840
EKKPSSVRAL SIVLPIVLLV FLCLGVFLLW KNWRLKNINS
References
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sources:
Genetic association of low density lipoprotein
receptor and Alzheimer's disease. (2005)
The modular adaptor protein ARH is required for
low density lipoprotein (LDL)binding and
internalization but not for LDL receptor clustering
in coated pits. (2004)
Molecular characterization of familial
hypercholesterolemia in Spain: identificationof 39
novel and 77 recurrent mutations in LDLR. (2004)
Harmful effects of increased LDLR expression in
micewith human APOE*4 butnot APOE*3. (2004)
Estrogen receptor-alpha and Sp1 interact in the
induction of the low densitylipoproteinreceptor. (2003)
Generation and initial analysis of more than 15,000
full-length human and mouse cDNA
References
Comparison of apolipoprotein B metabolism
in familial defective apolipoproteinB and
heterogeneous familial
hypercholesterolemia. (2002)
 Molecular basis of familial
hypercholesterolemia in Brazil:
Identificationof seven novel LDLR gene
mutations. (2002)
 Identification of Egr1 as the oncostatin Minduced transcription activatorthat binds
to sterol-independent regulatory element
of human LDL receptor promoter. (2002)
 Sequencing of the coding exons of the LRP1
and LDLR genes on individual DNA samples
reveals novel mutations in both
genes. (2001)
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