title: A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1.
abstract: 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.
authors.affiliation: INSERM U781, Université Paris Descartes, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Marques-Pinheiro
authors.forename: Marie
authors.initials: M
authors.lastname: Marduel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
authors.forename: Martine
authors.initials: M
authors.lastname: Devillers
authors.forename: Ludovic
authors.initials: L
authors.lastname: Villéger
authors.forename: Delphine
authors.initials: D
authors.lastname: Allard
authors.forename: Jean
authors.initials: J
authors.lastname: Weissenbach
authors.forename: Maryse
authors.initials: M
authors.lastname: Guerin
authors.forename: Yassine
authors.initials: Y
authors.lastname: Zair
authors.forename: Danièle
authors.initials: D
authors.lastname: Erlich
authors.forename: Claudine
authors.initials: C
authors.lastname: Junien
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jaïs
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005192:Family Health; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D055815:Young Adult