Genetic diagnosis of familial hypercholesterolaemia: The importance of functional analysis of potential splice-site mutations

Journal of Medical Genetics

Volumn 46, Issue 5, 2009, Pages 352-357

  Bourbon, M ^a   Duarte, M A ^a   Alves, A C ^a   Medeiros, A M ^a   Marques, L ^a   Soutar, A K ^b  

^a NATIONAL INSTITUTE OF HEALTH DR RICARDO JORGE   (Portugal)

^b HAMMERSMITH HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

LOW DENSITY LIPOPROTEIN RECEPTOR; MESSENGER RNA;

ADOLESCENT; ADULT; AGED; ARTICLE; ASSAY; BLOOD CELL; BLOOD DONOR; CELL ISOLATION; CHILD; CLINICAL ARTICLE; CONTROLLED STUDY; DIAGNOSTIC ERROR; EXON; FAMILIAL HYPERCHOLESTEROLEMIA; FEMALE; FOLLOW UP; GENE MUTATION; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HUMAN; HUMAN CELL; INTRON; MALE; MONONUCLEAR CELL; MUTATIONAL ANALYSIS; PORTUGAL; PRESCHOOL CHILD; PRIORITY JOURNAL; PROMOTER REGION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA SPLICING; SCHOOL CHILD;

ADOLESCENT; ADULT; BASE SEQUENCE; CHILD; CHILD, PRESCHOOL; DNA MUTATIONAL ANALYSIS; FEMALE; HUMANS; HYPERLIPOPROTEINEMIA TYPE II; MALE; MIDDLE AGED; MUTATION; PEDIGREE; PORTUGAL; RECEPTORS, LDL; RNA SPLICE SITES;

EID: 66249138829     PISSN: 00222593     EISSN: 14686244     Source Type: Journal    
DOI: 10.1136/jmg.2007.057000     Document Type: Article

References (31)

1. Goldstein JL, Hobbs HH, Brown MS. The metabolic and molecular bases of inherited disease, 8th edn. New York: McGraw Hill, 2001;1:1981-2030.
2. Webb JC, Patel DD, Shoulders CC, Knight BL, Soutar AK. Genetic variation at a splicing branch point in intron 9 of the low density lipoprotein (LDL)-receptor gene: a rare mutation that disrupts mRNA splicing in a patient with familial hypercholesterolaemia and a common polymorphism. Hum Mol Genet 1996;5:1325-31.
3. Graham CA, Mcllhatton BP, Kirk CW, Beattie ED, Lyttle K, Hart P, Neely RD, Young IS, Nicholls DP. Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate. Atherosclerosis 2005;182:331-40.
4. Bourbon M, Sun XM, Soutar AK. A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing. Atherosclerosis 2007;195:e17-20.
5. Shapiro MB, Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 1987;15:7155-74.
6. Florea L, Di Francesco V, Miller J, Turner R, Yao A, Harris M, Walenz B, Mobarry C, Merkulov GV, Charlab R, Dew I, Deng Z, Istrail S, Li P, Sutton G. Gene and alternative splicing annotation with AIR. Genome Res 2005;15:54-66.
7. Churbanov A, Rogozin IB, Deogun JS, Ali H. Method of predicting splice sites based on signal interactions. Biol Direct 2006;1:10.
8. Sun XM, Patel DD, Bhatnagar D, Knight BL, Soutar AK. Characterization of a splice- site mutation in the gene for the LDL receptor associated with an unpredictably severe clinical phenotype in English patients with heterozygous FH. Arterioscler Thromb Vasc Biol 1995;15:219- 27.
9. Bourbon M, Rato Q. Portuguese Familial Hypercholesterolemia Study: presentation of the study and preliminary results. Rev Port Cardiol 2006;25:999-1013.
10. Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK. Atherosclerosis 2007;196:633-42.
11. Lombardi MP, Redeker EJ, Defesche JC, Kamerling SW, Trip MD, Mannens MM, Havekes LM, Kastelein JJ. Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands. Clin Genet 2000;57:1 16-24.
12. Jensen HK, Jensen LG, Hansen PS, Faergeman 0, Gregersen N. High sensitivity of the single-strand conformation polymorphism method for detecting sequence variations in the low-density lipoprotein receptor gene validated by DNA sequencing. Clin Chem 1996;42:1140-6.
13. Mozas P, Cenarro A, Civeira F, Castillo S, Ros E, Pocovi M. Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: identification of 3 novel mutations in the LDL receptor gene. Hum Mutat 2000;15:483-4.
14. Wang J, Ban MR, Hegele RA. Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia. J Lipid Res 2005;46:366-72.
15. Alharbi KK, Aldahmesh MA, Spanakis E, Haddad L, Whittall RA, Chen XH, Rassoulian H, Smith MJ, Sillibourne J, Ball NJ, Graham NJ, Briggs PJ, Simpson IA, Phillips DI, Lawlor DA, Ye S, Humphries SE, Cooper C, Smith GD, Ebrahim S, Eccles DM, Day IN. Mutation scanning by meltMADGE: validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population. Genome Res 2005;15:967-77.
16. Lombardi P, Sijbrands EJ, Kamerling S, Leuven JA, Havekes LM. The T705I mutation of the low density lipoprotein receptor gene (FH Paris-9) does not cause familial hypercholesterolemia. Hum Genet 1997;99:106-7.
17. Heath KE, Whittal RA, Miller GJ, Humphries S. I705 variant in the low denisty lipoprotein receptor gene has no effect on plasma cholesterol levels. J Med Genet 2000;37:713-15.
18. Amsellem S, Briffaut D, Carrié A, Rabés JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P. Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. Hum Genet 2002;111:501-10.
19. Dedoussis GV, Skoumas J, Pitsavos C, Choumerianou DM, Genschel J, Schmidt H, Stefanadis C. FH clinical phenotype in Greek patients with LDL-R defective vs. negative mutations. Eur J Clin Invest 2004;34:402-9.
20. Whittall RA, Matheus S, Cranston T, Miller GJ, Humphries SE. The intron 14 2140+5G>A variant in the low density lipoprotein receptor gene has no effect on plasma cholesterol levels. J Med Genet 2002;39:e57.
21. Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992;1:445-66.
22. Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M. Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. Hum Mutat 2004;24:187.
23. Reese MG, Eeckman FH, Kulp D, Haussler D. Improved splice site detection in Genie. J Comput Biol 1997;4:311-23.
24. Tveten K, Ranheim T, Berge KE, Leren TP, Kulseth MA. Analysis of alternatively spliced isoforms of human LDL receptor mRNA. Clin Chim Acta 2006;3:151-7.
25. Zhu H, Tucker HM, Grear KE, Simpson JF, Manning AK, Cupples LA, Estus S. A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum Mol Genet 2007;16:1765-72.
26. Mozas P, Galetto R, Albajar M, Ros E, Pocovi M, Rodriguez-Rey JC. A mutation (-49C>T) in the promoter of the low density lipoprotein receptor gene associated with familial hypercholesterolemia. J Lipid Res 2002;43:13-18.
27. Jensen LG, Jensen HK, Nissen H, Kristiansen K, Faergeman 0, Bolund L, Gregersen N. An LDL receptor promoter mutation in a heterozygous FH patient with dramatically skewed ratio between the two allelic mRNA variants. Hum Mutat 1996;7:82-4.
28. Lombardi P, Hoffer MJ, Top B, de Wit E, Gevers Leuven JA, Frants RR, Havekes LM. An acceptor splice site mutation in intron 16 of the low density lipoprotein receptor gene leads to an elongated, internalization defective receptor. Atherosclerosis 1993;104:117-28.
29. Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR. ESEfinder: A web resource to identify exonic splicing enhancers. Nucleic Acids Res 2003;31:3568-71.
30. Fairbrother WG, Yeo GW, Yeh R, Goldstein P, Mawson M, Sharp PA, Burge CB. RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. Nucleic Acids Res 2004;32:W187-90.
31. Fairbrother WG, Yeh RF, Sharp PA, Burge CB. Predictive identification of exonic splicing enhancers in human genes. Science 2002;297:1007-13.