J Med Assoc Thai 2000; 83 (11):81

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Mutation Analysis of Exon 9 of the LDL Receptor Gene in Thai Subjects with Primary Hypercholesterolemia
Yamwong P Mail, Pongrapeeporn KS , Thepsuriyanont P , Amomrattana A , Somkasettrin A , Sribhen K

The low density lipoprotein (LDL) receptor plays an important role in cholesterol homeo-
stasis. A mutation in this gene causes an autosomal codominant disorder, namely familial
hypercholesterolemia (FH). In this study, single strand conformation polymorphism (SSCP) analy-
sis was used to screen for mutations in exon 9 of the LDL receptor gene in a group of 45 Thai
patients (11 males and 34 females) with primary hypercholesterolemia. The peptide encoded by
exon 9 belongs to the epidermal growth factor (EGF) precursor homology domain which is highly
conserved in the LDL receptor protein. An abnormal SSCP pattern was observed in one female
patient. The same screening strategy was also used to screen DNA samples from 33 normolipi-
demic subjects. All of these samples showed normal SSCP pattern. By direct DNA sequencing, the
underlying mutation in the DNA with abnormal SSCP pattern was identified. The index subject
was heterozygous for a T to C transition at nucleotide 1235. This transition would cause a noncon-
servative substitution of a nonpolar side chain amino acid "methionine" at codon 391, with an
uncharged polar side chain amino acid "threonine", note M391T. From multiple amino acid
sequence alignment in six species, the amino acid at codon 391 and the others nearby are com-
pletely conserved. Such nonconservative substitution of an amino acid residue in a highly con-
served region could consequently result in a functional and/or structural defect in the receptor
protein. In conclusion, we propose that M391 T is likely to be the cause of hypercholesterolemia in
this index subject.
Key word : Hypercholesterolemia, LDL Receptor Gene, Mutation

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