TY - JOUR
T1 - The genetic spectrum of familial hypercholesterolemia in Pakistan
AU - Ahmed, Waqas
AU - Whittall, Ros
AU - Riaz, Moeen
AU - Ajmal, Muhammad
AU - Sadeque, Ahmed
AU - Ayub, Humaira
AU - Qamar, Raheel
AU - Humphries, Steve E.
PY - 2013/6/5
Y1 - 2013/6/5
N2 - Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes coding for the low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type-9 (PCSK9) or apo-lipoprotein B-100 (APOB). The aim of the present work was to determine the genetic basis of dyslipidemia in 11 unrelated Pakistani families. Methods: High resolution melting (HRM), sequencing and restriction fragment length polymorphism (RFLP). Results: Probands were screened for the promoter and all coding regions, including intron/exon boundaries, of LDLR and PCSK9 and part of exon 26 of APOB including p.(R3527Q). Two families were identified with previously unreported LDLR mutations (c.1019_1020delinsTG, p.(C340L) and c.1634G>A, p.(G545E)). Both probands had tendon xanthomas or xanthelasma and/or a history of cardiovascular disease. Co-segregation with hypercholesterolemia was demonstrated in both families. In silico studies predicted these variations to be damaging. In two families, novel PCSK9 variations were identified (exon2; c.314G. >. A, p.(R105Q) and exon3; c.464C>T, p.(P155L)). In silico studies suggested both were likely to be damaging, and family members carrying the p.(105Q) allele had lower total cholesterol levels, suggesting this is a loss-of-function mutation. For c.464C>T p.(P155L) the small number of relatives available precluded any strong inference. Conclusion: This report brings to seven the number of different LDLR mutations reported in FH patients from Pakistan and, as expected in this heterogeneous population, no common LDLR mutation has been identified.
AB - Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes coding for the low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type-9 (PCSK9) or apo-lipoprotein B-100 (APOB). The aim of the present work was to determine the genetic basis of dyslipidemia in 11 unrelated Pakistani families. Methods: High resolution melting (HRM), sequencing and restriction fragment length polymorphism (RFLP). Results: Probands were screened for the promoter and all coding regions, including intron/exon boundaries, of LDLR and PCSK9 and part of exon 26 of APOB including p.(R3527Q). Two families were identified with previously unreported LDLR mutations (c.1019_1020delinsTG, p.(C340L) and c.1634G>A, p.(G545E)). Both probands had tendon xanthomas or xanthelasma and/or a history of cardiovascular disease. Co-segregation with hypercholesterolemia was demonstrated in both families. In silico studies predicted these variations to be damaging. In two families, novel PCSK9 variations were identified (exon2; c.314G. >. A, p.(R105Q) and exon3; c.464C>T, p.(P155L)). In silico studies suggested both were likely to be damaging, and family members carrying the p.(105Q) allele had lower total cholesterol levels, suggesting this is a loss-of-function mutation. For c.464C>T p.(P155L) the small number of relatives available precluded any strong inference. Conclusion: This report brings to seven the number of different LDLR mutations reported in FH patients from Pakistan and, as expected in this heterogeneous population, no common LDLR mutation has been identified.
KW - Consanguinity
KW - Familial hypercholesterolemia
KW - HRM
KW - LDLR
KW - PCSK9
KW - Xanthomas
UR - http://www.scopus.com/inward/record.url?scp=84876447623&partnerID=8YFLogxK
U2 - 10.1016/j.cca.2013.03.017
DO - 10.1016/j.cca.2013.03.017
M3 - Article
C2 - 23535506
AN - SCOPUS:84876447623
SN - 0009-8981
VL - 421
SP - 219
EP - 225
JO - Clinica Chimica Acta
JF - Clinica Chimica Acta
ER -