Familial Hypercholesterolemia: The Lipids or the Genes?

Nutrition & Metabolism

Table 2 Gene defects involved in FH and their effect on the phenotype

Gene	Exon	Number of Sequence Variants	Function/Protein Domain	Effect on the Phenotype
LDLR	1	79	Signal sequence to the ER
	2	82	LDL-binding domain
	3	125
	4	339		Gene dosage effect
	5	71
	6	91		Homozygous → severe, resistant to therapy; death
	7	105	EGF-precursor like domain
	8	106
	9	145		Heterozygous → variable; depends on mutation.
	10	110
	11	77
	12	96		among all other genetic causes of FH
	13	72
	14	100
	15	41	OLS	environmental, and other metabolic factors.
	16	38	Transmembrane
	17	60
			Cytoplasmic
	18	4
ApoB	26	3*	Binding region to the LDLR	Less severe phenotype than LDLR mutations
PCSK9	1	32
	2	17	Enhanced binding to LDLR	Gain of function mutations cause
		hypercholesterolemia
	3	5
		Loss of function mutations cause
	4	14		hypocholesterolemia
	5	22		Polymorphisms in PCSK9 can affect the phenotype
		of FH patients in different populations (modifier gene)
	6	4
	7	7
	8	12
	9	18
	10	9
	11	5
	12	16
LDLRAP1/ARH	1	14
	2	1		Can be similar to classical homozygous FH, but has
		been reported to be less severe in general
	3	1
	Phosphotyrosine-binding	More variable phenotype
	4	6	(PTB) domain, which is the
	functional domain
	5	2	responsible for cholesterol
	metabolism
	6	8		More responsive to lipid-lowering therapy
	7	6
	8	1

*Many sequence variants exist in the ApoB gene. Only sequence variants involved in FH are mentioned here.

ISSN: 1743-7075