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Cited by 115Lipoproteins and Cardiovascular HealthLipid metabolism and disordersGenomics and Rare Diseases

Molecular spectrum of autosomal dominant hypercholesterolemia in France

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Marduel, Marie, Carrié, Alain, Sassolas, Agnes, Devillers, Martine, Carreau, Valérie, Di Filippo, Mathilde, Erlich, Danièle, Abifadel, Marianne +6 more·2010·Human Mutation
DOI 10.1002/humu.21348PMC PMC3152176
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Abstract

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9(proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France.Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly,175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations:FH=PCSK9>FDB>«Others» genes. The respective contribution of each known gene to ADH inthis French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands,no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes.

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  • At least 19% of ADH families have disease not associated with a mutation within LDLR, APOB or PCSK9.

    “at least 19% of ADH families in which the disease is not associated with a mutation within one of these three genes (Marduel M 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 Marduel M et al. 2010

    The Results and Discussion report that no mutation in LDLR, APOB or PCSK9 was identified in 258 of 1,358 French ADH probands (19.0%). This supports the percentage for that cohort, but the claim extends it to ADH families generally and treats an unidentified mutation as evidence that no mutation in those genes is associated with their disease. (LLM, conf=0.85)

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Research works printed but not linked: 28

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Authors
Marduel, M., Carrié, A., Sassolas, A., Devillers, M., Carreau, V., Di Filippo, M., Erlich, D., Abifadel, M., Marques-Pinheiro, A., Munnich, A., Junien, C., Boileau, C., Varret, M., & Rabès, J.-P.
Affiliations
  • Inserm (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Pitié-Salpêtrière Hospital (FR)
Corresponding author
Rabès, Jean-Pierre
ORCID
Venue
Human Mutation
Publisher
Hindawi Limited
Published
2010-08-31
Volume
31
Issue
11
Pages
E1811-E1824
ISSN
1059-7794 (ISSN-L)
DOI
10.1002/humu.21348
PMC
PMC3152176
OpenAlex
W1990298974
Cited by
115
References
0
Citations by year
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FWCI
12.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Mutation (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • 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)
  • Saint Joseph University
  • Fondation de France
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
autosomal dominant hypercholesterolemia, LDLR mutations, APOB mutations, PCSK9 mutations, LDL receptor, apolipoprotein B, PCSK9, mutation spectrum, novel mutations, mutation severity, French population, genetic heterogeneity
MeSH terms
Proprotein Convertase 9, Apolipoproteins B, Cholesterol, DNA Mutational Analysis, Female, France, Humans, Hyperlipoproteinemia Type II, Male, Mutation, Receptors, LDL, Serine Endopeptidases, Genetic Variation, Cohort Studies, Proprotein Convertases

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