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Genetic diagnosis of familial hypercholesterolaemia: a mutation and a rare non-pathogenic amino acid variant in the same family

      Abstract

      Familial hypercholesterolaemia (FH), a relatively common inherited disorder, is caused by mutations in the gene for the low density lipoprotein (LDL) receptor (LDLR) that result in impaired clearance of LDL. Identification of mutations in patients with the clinical phenotype of FH allows unequivocal diagnosis in potentially affected relatives, but depends critically on distinguishing mutations that affect protein function from variants with no significant effect. A presumed functional mutation in LDLR (G198D in exon 4) was identified in two hypercholesterolaemic English brothers by high throughput screening and was not found in 550 controls. However, a second variant (L458P) was identified separately in their mother that co-segregated with hypercholesterolaemia in the entire pedigree. L458, but not G198, is strongly conserved between species and lies in a region important for β-propeller stability. G198D was inherited from their normolipidaemic father by two of three siblings heterozygous for L458P; they appeared less severely hypercholesterolaemic and more responsive to statins than the third affected brother and their mother. This study emphasises that apparent co-segregation of an amino acid substitution in a critical region of the protein with hypercholesterolaemia and its absence from a large control population is insufficient evidence that a variant of the LDL receptor is necessarily deleterious to its function.

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      References

      1. Goldstein JL, Hobbs H, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 7th ed. New York: McGraw-Hill; 1995. p. 1981–2030.

        • Betteridge D.J
        • Broome K
        • Durrington P.N
        • et al.
        Scientific steering committee on behalf of the simon broome register group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management.
        Atherosclerosis. 1999; 142: 105-112
        • Sidhu P.S
        • Naoumova R.P
        • Maher V.M
        • et al.
        The extracranial carotid artery in familial hypercholesterolaemia: relationship of intimal-medial thickness and plaque morphology with plasma lipids and coronary heart disease.
        J. Cardiovasc. Risk. 1996; 3: 61-67
        • Raal F.J
        • Pilcher G.J
        • Waisberg R
        • Buthelezi E.P
        • Veller M.G
        • Joffe B.I
        Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia.
        Am. J. Cardiol. 1999; 83: 1330-1333
        • Marks D
        • Thorogood M
        • Neil H.A
        • Humphries S.E
        A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.
        Atherosclerosis. 2003; 168: 1-14
        • Kwiterovich P.O
        Identification and treatment of heterozygous familial hypercholesterolemia in children and adolescents.
        Am. J. Cardiol. 1993; 72: D30-D37
        • Leonard J.V
        • Wolfe O.H
        • Lloyd J
        • Whitelaw A
        • Slack J
        Diagnosing familial hypercholesterolaemia in childhood.
        Br. Med. J. 1977; 2: 455-456
        • Sun X.M
        • Patel D.D
        • Knight B.L
        • Soutar A.K
        Influence of genotype at the low density lipoprotein (LDL) receptor gene locus on the clinical phenotype and response to lipid-lowering drug therapy in heterozygous familial hypercholesterolaemia. The Familial Hypercholesterolaemia Regression Study Group.
        Atherosclerosis. 1998; 136: 175-185
        • Sun X.M
        • Patel D.D
        • Knight B.L
        • Soutar A.K
        Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia. The Familial Hypercholesterolaemia Regression Study Group.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3092-3101
        • Whittall R
        • Gudnason V
        • Weavind G.P
        • Day L.B
        • Humphries S.E
        • Day I.N.M
        Utilities for high throughput use of the single strand conformational polymorhism method: screening of 791 patients with familial hyperecholesterolaemia for mutations in exon 3 of the low density lipoprotein receptor gene.
        J. Med. Genet. 1995; 32: 509-515
        • Heath K.E
        • Humphries S.E
        • Middleton-Price H
        • Boxer M
        A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom.
        Eur. J. Hum. Genet. 2001; 9: 244-252
        • Umans-Eckenhausen M.A
        • Sijbrands E.J
        • Kastelein J.J
        • Defesche J.C
        Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population.
        Circulation. 2002; 106: 3031-3036
        • Thompson G.R
        • Seed M
        • Niththyananthan S
        • McCarthy S
        • Thorogood M
        Genotypic and phenotypic variation in familial hypercholesterolemia.
        Arteriosclerosis. 1989; 9: I75-I80
        • Miller G.J
        • Bauer K.A
        • Barzegar S
        • Cooper J.A
        • Rosenberg R.D
        Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease.
        Thromb. Haemost. 1996; 75: 767-771
        • Humphries S.E
        • Talmud P.J
        • Hawe E
        • Bolla M
        • Day I.N
        • Miller G.J
        Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study.
        Lancet. 2001; 358: 115-119
        • Oefner P.J
        • Underhill P.A
        Comparative DNA sequencing by denaturing high-performance liquid cromatography (DHPLC).
        Am. J. Hum. Genet. 1995; 57: A266
        • Jeon H
        • Meng W
        • Takagi J
        • Eck M.J
        • Springer T.A
        • Blacklow S.C
        Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair.
        Nat. Struct. Biol. 2001; 8: 499-504
        • Myant N.B
        Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia.
        Atherosclerosis. 1993; 104 ([published erratum appears in Atherosclerosis 1994;105(2):253]): 1-18
        • Abifadel M
        • Varret M
        • Rabes J.P
        • et al.
        Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
        Nat. Genet. 2003; 34: 154-156
        • Soutar A.K
        • Naoumova R.P
        • Traub L.M
        Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1963-1970
        • Villeger L
        • Abifadel M
        • Allard D
        • et al.
        The UMD-LDLR database: additions to the software and 490 new entries to the database.
        Hum. Mutat. 2002; 20: 81-87
        • Lombardi P
        • Sijbrands E.J
        • Kamerling S
        • Leuven J.A
        • Havekes L.M
        The T705I mutation of the low density lipoprotein receptor gene (FH Paris-9) does not cause familial hypercholesterolemia.
        Hum. Genet. 1997; 99: 106-107
        • Heath K.E
        • Whittall R.A
        • Miller G.J
        • Humphries S.E
        I705 variant in the low density lipoprotein receptor gene has no effect on plasma cholesterol levels.
        J. Med. Genet. 2000; 37: 713-715
        • Webb J.C
        • Patel D.D
        • Shoulders C.C
        • Knight B.L
        • Soutar A.K
        Genetic variation at a splicing branch point in intron 9 of the low density lipoprotein (LDL)-receptor gene: a rare mutation that disrupts mRNA splicing in a patient with familial hypercholesterolaemia and a common polymorphism.
        Hum. Mol. Genet. 1996; 5: 1325-1331
        • Webb J.C
        • Sun X.M
        • Patel D.D
        • McCarthy S.N
        • Knight B.L
        • Soutar A.K
        Characterization of two new point mutations in the low density lipoprotein receptor genes of an English patient with homozygous familial hypercholesterolemia.
        J. Lipid Res. 1992; 33: 689-698