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. 1999 May;64(5):1378–1387. doi: 10.1086/302370

A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.

M Varret 1, J P Rabès 1, B Saint-Jore 1, A Cenarro 1, J C Marinoni 1, F Civeira 1, M Devillers 1, M Krempf 1, M Coulon 1, R Thiart 1, M J Kotze 1, H Schmidt 1, J C Buzzi 1, G M Kostner 1, S Bertolini 1, M Pocovi 1, A Rosa 1, M Farnier 1, M Martinez 1, C Junien 1, C Boileau 1
PMCID: PMC1377874  PMID: 10205269

Abstract

Autosomal dominant hypercholesterolemia (ADH), one of the most frequent hereditary disorders, is characterized by an isolated elevation of LDL particles that leads to premature mortality from cardiovascular complications. It is generally assumed that mutations in the LDLR and APOB genes account for ADH. We identified one large French pedigree (HC2) and 12 additional white families with ADH in which we excluded linkage to the LDLR and APOB, implicating a new locus we named "FH3." A LOD score of 3.13 at a recombination fraction of 0 was obtained at markers D1S2892 and D1S2722. We localized the FH3 locus to a 9-cM interval at 1p34.1-p32. We tested four regional markers in another set of 12 ADH families. Positive LOD scores were obtained in three pedigrees, whereas linkage was excluded in the others. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB ADH families and implied a fourth locus. Radiation hybrid mapping located four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3. Our results show that ADH is genetically more heterogeneous than conventionally accepted.

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Selected References

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  1. Collod G., Babron M. C., Jondeau G., Coulon M., Weissenbach J., Dubourg O., Bourdarias J. P., Bonaïti-Pellié C., Junien C., Boileau C. A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet. 1994 Nov;8(3):264–268. doi: 10.1038/ng1194-264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  3. Edwards J. H. Exclusion mapping. J Med Genet. 1987 Sep;24(9):539–543. doi: 10.1136/jmg.24.9.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Goldstein J. L., Brown M. S. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974 Aug 25;249(16):5153–5162. [PubMed] [Google Scholar]
  5. Harrington C. R., Louwagie J., Rossau R., Vanmechelen E., Perry R. H., Perry E. K., Xuereb J. H., Roth M., Wischik C. M. Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease. Am J Pathol. 1994 Dec;145(6):1472–1484. [PMC free article] [PubMed] [Google Scholar]
  6. He Z., Yamamoto R., Furth E. E., Schantz L. J., Naylor S. L., George H., Billheimer J. T., Strauss J. F., 3rd cDNAs encoding members of a family of proteins related to human sterol carrier protein 2 and assignment of the gene to human chromosome 1 p21----pter. DNA Cell Biol. 1991 Oct;10(8):559–569. doi: 10.1089/dna.1991.10.559. [DOI] [PubMed] [Google Scholar]
  7. Innerarity T. L., Weisgraber K. H., Arnold K. S., Mahley R. W., Krauss R. M., Vega G. L., Grundy S. M. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6919–6923. doi: 10.1073/pnas.84.19.6919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kim D. H., Magoori K., Inoue T. R., Mao C. C., Kim H. J., Suzuki H., Fujita T., Endo Y., Saeki S., Yamamoto T. T. Exon/intron organization, chromosome localization, alternative splicing, and transcription units of the human apolipoprotein E receptor 2 gene. J Biol Chem. 1997 Mar 28;272(13):8498–8504. doi: 10.1074/jbc.272.13.8498. [DOI] [PubMed] [Google Scholar]
  9. Kong A., Cox N. J. Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet. 1997 Nov;61(5):1179–1188. doi: 10.1086/301592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  11. Law S. W., Lackner K. J., Hospattankar A. V., Anchors J. M., Sakaguchi A. Y., Naylor S. L., Brewer H. B., Jr Human apolipoprotein B-100: cloning, analysis of liver mRNA, and assignment of the gene to chromosome 2. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8340–8344. doi: 10.1073/pnas.82.24.8340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lestavel-Delattre S., Benhamamouch S., Agnani G., Luc G., Bard J. M., Brousseau T., Billardon C., Kusnierz J. P., De Gennes J. L., Fruchart J. C. Evidence of non-deficient low-density lipoprotein receptor patients in a pool of subjects with clinical familial hypercholesterolemia profile. Metabolism. 1994 Apr;43(4):397–402. doi: 10.1016/0026-0495(94)90066-3. [DOI] [PubMed] [Google Scholar]
  13. Lindgren V., Luskey K. L., Russell D. W., Francke U. Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8567–8571. doi: 10.1073/pnas.82.24.8567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Masana L., Joven J., Rubiés-Prat J., Lewis B. Low density lipoprotein metabolism and receptor studies in a patient with pseudohomozygous familial hypercholesterolaemia. Acta Paediatr Scand. 1990 Apr;79(4):475–476. doi: 10.1111/j.1651-2227.1990.tb11499.x. [DOI] [PubMed] [Google Scholar]
  15. Miserez A. R., Keller U. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995 Oct;15(10):1719–1729. doi: 10.1161/01.atv.15.10.1719. [DOI] [PubMed] [Google Scholar]
  16. Nissen H., Lestavel S., Hansen T. S., Luc G., Bruckert E., Clavey V. Mutation screening of the LDLR gene and ApoB gene in patients with a phenotype of familial hypercholesterolemia and normal values in a functional LDL receptor/apolipoprotein B assay. Clin Genet. 1998 Jul;54(1):79–82. doi: 10.1111/j.1399-0004.1998.tb03699.x. [DOI] [PubMed] [Google Scholar]
  17. O'Connell J. R., Weeks D. E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nat Genet. 1995 Dec;11(4):402–408. doi: 10.1038/ng1295-402. [DOI] [PubMed] [Google Scholar]
  18. Ohba T., Rennert H., Pfeifer S. M., He Z., Yamamoto R., Holt J. A., Billheimer J. T., Strauss J. F., 3rd The structure of the human sterol carrier protein X/sterol carrier protein 2 gene (SCP2). Genomics. 1994 Nov 15;24(2):370–374. doi: 10.1006/geno.1994.1630. [DOI] [PubMed] [Google Scholar]
  19. Ott J. Linkage analysis and family classification under heterogeneity. Ann Hum Genet. 1983 Oct;47(Pt 4):311–320. doi: 10.1111/j.1469-1809.1983.tb01001.x. [DOI] [PubMed] [Google Scholar]
  20. Pajukanta P., Nuotio I., Terwilliger J. D., Porkka K. V., Ylitalo K., Pihlajamäki J., Suomalainen A. J., Syvänen A. C., Lehtimäki T., Viikari J. S. Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23. Nat Genet. 1998 Apr;18(4):369–373. doi: 10.1038/ng0498-369. [DOI] [PubMed] [Google Scholar]
  21. Phelan C. M., Larsson C., Baird S., Futreal P. A., Ruttledge M. H., Morgan K., Tonin P., Hung H., Korneluk R. G., Pollak M. N. The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and mutation analysis in human breast tumors. Genomics. 1996 May 15;34(1):63–68. doi: 10.1006/geno.1996.0241. [DOI] [PubMed] [Google Scholar]
  22. Reed P. W., Davies J. L., Copeman J. B., Bennett S. T., Palmer S. M., Pritchard L. E., Gough S. C., Kawaguchi Y., Cordell H. J., Balfour K. M. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nat Genet. 1994 Jul;7(3):390–395. doi: 10.1038/ng0794-390. [DOI] [PubMed] [Google Scholar]
  23. Sun X. M., Patel D. D., Knight B. L., Soutar A. K. Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia. The Familial Hypercholesterolaemia Regression Study Group. Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3092–3101. doi: 10.1161/01.atv.17.11.3092. [DOI] [PubMed] [Google Scholar]
  24. Varret M., Rabès J. P., Collod-Béroud G., Junien C., Boileau C., Béroud C. Software and database for the analysis of mutations in the human LDL receptor gene. Nucleic Acids Res. 1997 Jan 1;25(1):172–180. doi: 10.1093/nar/25.1.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Varret M., Rabés J. P., Thiart R., Kotze M. J., Baron H., Cenarro A., Descamps O., Ebhardt M., Hondelijn J. C., Kostner G. M. LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis. Nucleic Acids Res. 1998 Jan 1;26(1):248–252. doi: 10.1093/nar/26.1.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wojciechowski A. P., Farrall M., Cullen P., Wilson T. M., Bayliss J. D., Farren B., Griffin B. A., Caslake M. J., Packard C. J., Shepherd J. Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24. Nature. 1991 Jan 10;349(6305):161–164. doi: 10.1038/349161a0. [DOI] [PubMed] [Google Scholar]
  27. Wong W. T., Kraus M. H., Carlomagno F., Zelano A., Druck T., Croce C. M., Huebner K., Di Fiore P. P. The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32. Oncogene. 1994 Jun;9(6):1591–1597. [PubMed] [Google Scholar]
  28. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]

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