Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico.
BACKGROUND
Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apoB) genes, respectively. A third locus on chromosome 1p34.1-p32 was recently linked to FH and the responsible gene has been identified [protein convertase subtilisin/kexin type 9 (PCSK9)].


METHODS
We assessed the contribution of the LDLR, apoB, and PCSK9 genes as cause of FH in Mexico. Forty six unrelated probands, as well as 68 affected and 60 healthy relatives, were included.


RESULTS
All index cases were diagnosed as having heterozygous autosomal dominant FH. Seventeen of the 46 index cases had LDLR gene mutations, four of which were novel (Fs92ter108, C268R, Q718X, and Fs736ter743); and only one patient had an apoB mutation (R3500Q). We sequenced the PCSK9 gene in the remainder of the 28 probands with no identified LDLR or APOB gene defects; however, no PCSK9 mutations were found, including one large kindred with positive linkage to the 1p34.1-32 locus (multipoint LOD score of 3.3) and two small pedigrees. Linkage was excluded from these three loci in at least four kindreds suggesting that other yet uncharacterized genes are involved.


CONCLUSIONS
Our results underline substantial genetic heterogeneity for FH in the Mexican population.
Robles-Osorio
Ludivina
L
Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., Mexico.
Huerta-Zepeda
Alejandra
A
Ordóñez
Ma Luisa
ML
Canizales-Quinteros
Samuel
S
Díaz-Villaseñor
Andrea
A
Gutiérrez-Aguilar
Ruth
R
Riba
Laura
L
Huertas-Vázquez
Adriana
A
Rodríguez-Torres
Maribel
M
Gómez-Díaz
Rita A
RA
Salinas
Saul
S
Ongay-Larios
Laura
L
Codiz-Huerta
Guadalupe
G
Mora-Cabrera
Minerva
M
Mehta
Roopa
R
Gómez Pérez
Francisco J
FJ
Rull
Juan A
JA
Rabès
Jean-Pierre
JP
Tusié-Luna
Ma Teresa
MT
Durán-Vargas
Socorro
S
Aguilar-Salinas
Carlos A
CA
D000328:Adult; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008800:Mexico; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D040641:Quantitative Trait Loci; D011973:Receptors, LDL / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases