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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

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Familial Hypercholesterolemia

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  1. Familial Hypercholesterolemia Honors Genetics 2006

  2. 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

  3. Hypercholesterolemia Gel Results N FHC 1 2 3 marker

  4. 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

  5. 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. • 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.

  6. Cholesterol and the Steroid Rings

  7. Desirable cholesterol levels • Desirable — Less than 200 mg/dLBorderline high risk — 200–239 mg/dLHigh 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

  8. 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.

  9. 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 HDL-cholesterol is below 40 mg/dL, you are at substantially higher risk for heart disease. • The higher your HDL-cholesterol, the better. The average HDL-cholesterol for men is about 45 mg/dL, and for women it is about 55 mg/dL.

  10. Tests in the Lipid Profile • Total Cholesterol • HDL Cholesterol • LDL Cholesterol • VLDL Cholesterol • Triglycerides • Apolipoprotein A1Extended Lipid Profile. • Apolipoprotein B • Lipoprotein(a)

  11. Before withdrawing blood for lipid profile :- •      a. 12 - 14 hours fasting sample is required. •     b. Individuals should have been on their usual diet.

  12. Case Historyreferene - OMIM • 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.

  13. Chromosome – 19.13.2 • Start:11,061,132 bp from pterEnd:11,105,490 bp from pterSize:44,358 bases

  14. Gene Expression

  15. SNP – Single nucleotide polymorphism • 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

  16. 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

  17. Substitution mutations • GGG-AGG Gly-Arg Hypercholesterolaemia • GCG-GAG Ala-Glu Hypercholesterolaemia • CTC-CCC Leu-Pro Hypercholesterolaemia • cGAG-TAG Glu-Term Hypercholesterolaemia

  18. RCSB – The LDLR receptor

  19. Sequence for LDLR protein • 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 INFDNPVYQK TTEDEVHICH 850 860 NQDGYSYPSR QMVSLEDDVA

  20. References • 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 densitylipoprotein-receptor. (2003) • Generation and initial analysis of more than 15,000 full-length human and mouse cDNA

  21. 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 M-induced 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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