A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1
Open accessAbstract
Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated increase in plasmatic low-density lipoprotein (LDL) cholesterol levels associated with high risk of premature cardiovascular disease. Mutations in LDLR, APOB, and PCSK9 genes have been shown to cause ADH. We now report further genetic heterogeneity of ADH through the study of a large French family in which the involvement of these three genes was excluded. A genome-wide scan mapped the disease-causing gene, named HCHOLA4, at 16q22.1 in a 7.89-Mb interval containing 154 genes with a maximum LOD score of 3.9. To reduce the linked region, we genotyped 18 smaller non-LDLR/non-APOB/non-PCSK9-ADH families at the HCHOLA4 locus. Six families did not exclude linkage to the locus, but none allowed reduction of the disease interval. The 154 regional genes were sorted according to the function of the encoded protein and tissue expression profiles, and 57 genes were analyzed through sequencing of their coding region and close flanking intronic parts. No disease-causing mutation was identified in these families, particularly in the LCAT gene. Finally, our results also show the existence of other ADH genes as nine families were neither linked to LDLR, APOB, and PCSK9 genes nor to the new HCHOLA4 locus.
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Among 9 non-LDLR/-APOB/-PCSK9/-HCHOLA4 families identified, one was large enough to enable genome wide mapping of a new ADH gene.
“Among 9 non-LDLR/-APOB/-PCSK9/-HCHOLA4 families we have identified, one was large enough to enable genome wide mapping of a new ADH gene (Marques-Pinheiro A et al. 2010).”
From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the<i>APOE</i>p.Leu167del Mutation (2013) · cites this paper as Marques-Pinheiro A et al. 2010
The Abstract and Linkage analysis section distinguish the large family used to map HCHOLA4 from the nine families that excluded linkage to that locus. The paper therefore does not place the genome-mapped family among those nine; it says the opposite. Our copy provides no page numbers for these passages. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredNew ADH loci were recently mapped at 16q22.1 (HCHOLA4) and 8q24.22.
“new ADH loci were recently mapped at 16q22.1, HCHOLA4 (Marques-Pinheiro A et al. 2010), and 8q24.22 (Cenarro A et al. 2011).”
From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the<i>APOE</i>p.Leu167del Mutation (2013) · cites this paper as Marques-Pinheiro A et al. 2010
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Research works printed but not linked: 36
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Khalil, Y. A., Rabès, J.-P., Boileau, C., & Varret, M. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.007 · Cited by 170 · see citing works
Self-citationMarduel, M., Ouguerram, K., Serre, V., Bonnefont-Rousselot, D., Marques-Pinheiro, A., Erik Berge, K., Devillers, M., Luc, G., Lecerf, J.-M., Tosolini, L., et al. (2013) · Human Mutation · doi:10.1002/humu.22215 · Cited by 133 · see citing works
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- Authors
- The French Research Network on ADH, Marques-Pinheiro, A., Marduel, M., Rabès, J.-P., Devillers, M., Villéger, L., Allard, D., Weissenbach, J., Guerin, M., Zair, Y., Erlich, D., Junien, C., Munnich, A., Krempf, M., Abifadel, M., Jaïs, J.-P., Boileau, C., & Varret, M.
- Affiliations
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Varret, Mathilde
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2010-06-23
- Volume
- 18
- Issue
- 11
- Pages
- 1236-1242
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC2987478
- OpenAlex
- W2060843080
- Cited by
- 38
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 6 · 2012: 4
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Pfizer
- Agence Nationale de la Recherche (ANR-05-PCOD-0017, ANR-08-GENO-0002, ANR-08-GENO-002-01, ANR-06-MRAR-0038, ANR-05)
- Fondation de France
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- autosomal dominant hypercholesterolemia, genetic heterogeneity, LDL receptor, apolipoprotein B, PCSK9, lecithin:cholesterol acyltransferase, LDL cholesterol, family-based linkage analysis
- MeSH terms
- Adolescent, Adult, Aged, 80 and over, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 16, Family Health, Female, France, Humans, Hyperlipoproteinemia Type II, Lod Score, Male, Middle Aged, Pedigree, Genetic Predisposition to Disease, Genome-Wide Association Study, Young Adult
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