CYS127S (FH-Kairouan) and D245N (FH-Tozeur) mutations in the LDL receptor gene in Tunisian families with familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH, MIM 143890) is a dominantly inherited metabolic disorder caused by various mutations of the LDL receptor (LDL-R) gene causing delayed clearance of serum low density lipoproteins (LDL). The prevalence of homozygous FH has been estimated to be 1 in a million in European and North American populations. In central and southern Tunisia, the prevalence of homozygous FH is approximately seven-fold higher. The minimal estimated frequency of heterozygotes is about 1/160. These frequencies are as high as those found in populations with a high degree of inbreeding, such as Afrikaners in South Africa, Christian Lebanese, Finns, and French Canadians. In these populations, only a limited number of LDL-R gene mutations cause FH in the majority of affected cases as the result of a founder effect. Because of numerous consanguineous unions in rural areas in Tunisia, it can be predicted that the number of mutations causing FH may be limited. Moreover, we had reported that heterozygous FH might be misdiagnosed through classical symptom assessment because of mild clinical expression. Therefore, Tunisian patients with FH would be easier to identify by direct genotyping of frequent disease causing mutations. We have recently identified one founder frameshift mutation (FsI472; del TCT, ins AGAGACA, →43 aa-term) in five families originating from the coastal region of Monastir in Tunisia. The aim of this study was to characterise further the spectrum of LDL receptor gene mutations in the Tunisian population. In order to investigate the influence of potential modifier alleles on phenotypic expression of FH, apoE polymorphism and common LPL gene variants were analysed. Here we describe two novel missense mutations in the LDL-R gene causing FH in two unrelated families from central and southern Tunisia.