Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent.
Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease caused by mutations in the gene coding for the low density lipoprotein receptor (LDL-R). It is characterized by a high concentration of low density lipoprotein (LDL), which frequently gives rise to premature coronary artery disease. We studied the probands of five FH Sicilian families with 'definite' FH and one proband of Paraguayan descent with homozygous FH who has been treated with an effective living-donor liver transplantation. In order to seek the molecular defect in these six families, we used direct sequencing to define the molecular defects of the LDL-R gene responsible for the disease. We described three novel missense mutations (C100Y, C183Y and G440C), two frameshift mutations (g.1162delC in exon 8 and g.2051delC in exon 14) and one mutation (g.2390-1Gright curved arrow A) at splicing acceptor consensus sequences located in intron 16 of the LDL-R gene; the analysis of cDNA of this splicing mutation showed the activation of a cryptic splice site in intron 16 and the binding studies showed a reduction in internalisation of LDL-DIL in the proband's cultured fibroblasts. Moreover, a g.2051delC in exon 14 was identified in the proband of Paraguayan ancestry with clinical features of homozygous FH. The mutation identified in the South American patient represents the first description of a variant in South American patients other than Brazilian FH patients. The 5 mutations identified in the Sicilian patients confirm the heterogeneity of LDL-R gene mutations in Sicily.
Cefalù
Angelo B
AB
Department of Internal Medicine and Geriatrics, University of Palermo, Italy.
Barraco
Giacoma
G
Noto
Davide
D
Valenti
Vincenza
V
Barbagallo
Carlo M
CM
Elisir
Gerardo D
GD
Cuniberti
Luis A
LA
Werba
José P
JP
Libra
Massimo
M
Costa
Salvatore
S
Gianguzza
Fabrizio
F
Notarbartolo
Alberto
A
Travali
Salvatore
S
Averna
Maurizio R
MR
D000328:Adult; D001681:Biological Assay; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000208:ethnology* / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010239:Paraguay / Q000208:ethnology; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*; D012802:Sicily / Q000208:ethnology
D008055:Lipids; D012333:RNA, Messenger; D011973:Receptors, LDL