title: The genetic spectrum of familial hypercholesterolemia in Pakistan.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Waqas
authors.initials: W
authors.lastname: Ahmed
authors.forename: Ros
authors.initials: R
authors.lastname: Whittall
authors.forename: Moeen
authors.initials: M
authors.lastname: Riaz
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ajmal
authors.forename: Ahmed
authors.initials: A
authors.lastname: Sadeque
authors.forename: Humaira
authors.initials: H
authors.lastname: Ayub
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001055:Apolipoproteins B / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000503:physiopathology; D007438:Introns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D001055:Apolipoproteins B; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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