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HYPERCHOLESTEROLEMIA, FAMILIAL, 4; FHCL4

HYPERCHOLESTEROLEMIA, FAMILIAL, 4; FHCL4

Alternative titles; symbolsHYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE; ARHHYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 1, FORMERLY; ARH1, FORMERLYFHCB1, FORMERLYHYP...

Alternative titles; symbols

  • HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE; ARH
  • HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 1, FORMERLY; ARH1, FORMERLY
  • FHCB1, FORMERLY
  • HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 2, FORMERLY; ARH2, FORMERLY
  • FHCB2, FORMERLY

▼ Description

Autosomal recessive familial hypercholesterolemia-4 (FCHL4) is a rare monogenic disease characterized by very high levels of low-density lipoprotein (LDL) cholesterol (usually above 400 mg/dl) and increased risk of premature atherosclerotic cardiovascular disease (summary by Sanchez-Hernandez et al., 2018).

▼ Clinical Features

Zuliani et al. (1995) described a consanguineous Sardinian family in which a brother and sister had a severe form of hypercholesterolemia with the clinical features of familial hypercholesterolemia (FH; 143890) homozygotes, including severely elevated plasma low density lipoprotein (LDL) cholesterol, tuberous and tendon xanthomata, and premature atherosclerosis. However, LDL receptor (LDLR; 606945) activity measured in skin fibroblasts was normal, as was LDL binding ability. Haplotype segregation analysis excluded involvement of the LDLR and apolipoprotein B (APOB; 107730) genes in the pathogenesis of the disorder. Consanguinity, absence of vertical transmission, and bimodal distribution of plasma cholesterol levels in the kindred were consistent with autosomal recessive inheritance. Sitosterolemia (see 210250) and pseudohomozygous hyperlipidemia (see 144250) were ruled out.

Zuliani et al. (1999) identified a second Sardinian kindred with similar characteristics. The probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoB, sitosterolemia, and cholesteryl ester storage disease (278000) were excluded by in vitro studies. By LDL turnover studies, the authors found a marked reduction in the fractional catabolic rate and a significant increase in the production rate of LDL apoB in the probands compared with normolipidemic controls. The probands also showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote studied in parallel. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. These findings suggested that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appeared to be caused by a selective reduction in hepatic LDL uptake. Zuliani et al. (1999) proposed that in this new lipid disorder, a recessive defect causes a selective impairment of LDLR function in the liver. In a note added in proof, Zuliani et al. (1999) stated that 4 'new' Sardinian families with the characteristics of familial recessive hypercholesterolemia had been identified. In all probands, the LDLR activities in fibroblasts as well as the binding ability of LDL to the LDLR were normal.

Schmidt et al. (1998) identified a 38-year-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. They concluded that the disorder was autosomal recessive. Serum concentrations of cholesterol responded well to diet and statins. There was no evidence of an abnormal LDL-APOB particle, which was isolated from the patient by use of the U937 proliferation assay as a functional test of the LDL binding capacity. APOB-3500 and APOB-3531 defects were ruled out by PCR, and there was no evidence for a defect within the LDLR by skin fibroblast analysis, linkage analysis, SSCP, and Southern blot screening across the entire LDLR gene. The in vivo kinetics of radioiodinated LDL-APOB were evaluated in the proband and 3 normal controls. The LDL-APOB isolated from the patient showed normal catabolism, confirming an intact LDL particle. In contrast, the fractional catabolic rate of autologous LDL in the subject and normal controls revealed remarkably delayed catabolism of the patient's LDL. The elevation of LDL cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs 12.7 to 15.7 mg/kg per day. The authors concluded that there is another catabolic defect beyond the APOB and LDLR genes causing familial hypercholesterolemia.

Norman et al. (1999) identified apparently recessive familial hypercholesterolemia in 2 kindreds, one of Turkish origin and the other of Asian-Indian origin. The index patient of the Turkish family had a longstanding presumptive diagnosis of homozygous FH based on a raised plasma cholesterol concentration, the presence of extensive cutaneous xanthomata in the webs of her fingers and creases of her hands, and tendon xanthomata from an early age, as well as supravalvular aortic stenosis and premature coronary heart disease. The clinical characteristics of this woman were described in detail by Rallidis et al. (1996). A sib and a double first cousin were also affected. The affected individuals were the offspring of a first-cousin marriage in each case. All 4 parents were apparently unaffected. In the Asian-Indian family, 2 sisters were affected. The parents of this family were also reported to be first cousins, but no additional members of the family were available for study. Cells from the patients in these families exhibited no measurable degradation of LDL in culture. Extensive analysis of DNA and mRNA revealed no defect in the LDL receptor gene, and alleles of the LDLR and apolipoprotein B (APOB; 107730) genes did not cosegregate with hypercholesterolemia in these families. Fluorescence-activated cell sorting (FACS) analysis of binding and uptake of fluorescent LDL or anti-LDLR antibodies showed that LDL receptors were on the cell surface and bound LDL normally, but failed to be internalized, suggesting that some component of endocytosis through clathrin-coated pits was defective. Internalization of the transferrin receptor (190010) occurred normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization signal. Norman et al. (1999) concluded that identification of the defective gene would aid genetic diagnosis of other hypercholesterolemic patients and elucidate the mechanism by which LDL receptors are internalized, thus suggesting perhaps more appropriate methods of treatment then those currently used for FH patients with known genetic defects.

▼ Mapping

Eden et al. (2001) performed a genomewide scan with polymorphic genetic markers in the 2 families reported by Norman et al. (1999). In both pedigrees, a single region of approximately 12 cM on 1p36-p35, designated FHCB2, fulfilled the criteria for homozygous inheritance of alleles in the affected offspring but not their unaffected sibs. The combined lod score was 5.3 in these unrelated families.

Using 4 ARH families, including 2 previously studied by Zuliani et al. (1995, 1999), Garcia et al. (2001) mapped the ARH locus to a 1-cM interval on chromosome 1p35 extending from D1S1152 to D1S2885. Garcia et al. (2001) identified 6 mutations in a gene encoding a putative adaptor protein (LDLRAP1; 605747) mapping to this region. They found no linkage to 15q25-q26, the locus that Ciccarese et al. (2000) had found to be associated with ARH using one of the same families.

▼ Molecular Genetics

In affected individuals from 6 families with autosomal recessive hypercholesterolemia, including the 2 Sardinian families originally reported by Zuliani et al. (1995) and Zuliani et al. (1999) and a Lebanese family previously described by Khachadurian and Uthman (1973), as well as another Lebanese family, an Iranian family, and an American family, Garcia et al. (2001) identified homozygous mutations in the ARH gene (LDLRAP1; see 605747.0001-605747.0006). The nonsense mutation (W22X; 605747.0001) and 1-bp insertion (605747.0002) that were detected in the 2 original Sardinian families were also identified in homozygosity or compound heterozygosity in 10 additional unrelated Sardinian ARH probands, and neither mutation was found in 50 normolipidemic Sardinians. The authors suggested that the finding of 2 mutations accounting for ARH in 12 Sardinian families represented genetic drift on the island of Sardinia.

Arca et al. (2002) screened the entire coding sequence of LDLRAP1 in 40 unrelated individuals from around the world who had hypercholesterolemia and at least 1 normocholesterolemic parent. They identified 4 Italian probands who were homozygous for the same 1-bp insertion (605747.0002) that had previously been identified in Sardinian patients. No mutations were identified in the other 36 probands.

In a Syrian family with autosomal recessive hypercholesterolemia, Al-Kateb et al. (2002) found evidence for an interaction between loci on 1p36.1-p35 and 13q22-q32 (see cholesterol-lowering factor, 604595). They identified an intron 1 acceptor splice site mutation in the ARH gene (605747.0007) in this family.

In 2 Japanese sibs with ARH, Harada-Shiba et al. (2003) identified homozygosity for a 1-bp insertion in the LDLRAP1 gene (605747.0009).

In 2 affected sibs from a nonconsanguineous Mexican family with autosomal recessive hypercholesterolemia, Canizales-Quinteros et al. (2005) identified homozygosity for a donor splice site mutation in intron 4 of the ARH gene (605747.0008), resulting in a mutant protein with an altered phosphotyrosine-binding (PTB) domain. Both parents and an unaffected sister were heterozygous for the mutation.

Sanchez-Hernandez et al. (2018) reviewed data from the Dyslipidemia Registry of the Spanish Atherosclerosis Society, from published reports of Spanish patients with hypercholesterolemia, and from all diagnostic genetic studies for familial hypercholesterolemia in Spain. They identified 7 Spanish patients with ARH and mutations in the LDLRAP1 gene, including 2 sibs who were previously reported by Quagliarini et al. (2007). One patient, who was compound heterozygous for the missense mutations T218I (605747.0010) and S288L (605747.0011), exhibited a milder phenotype with much lower baseline LDL levels and later diagnosis than the other 6 patients, who were all homozygous for truncating mutations. Sanchez-Hernandez et al. (2018) concluded that ARH is a very rare disease in Spain, with a prevalence of 1 case per 6.5 million people.

Exclusion Studies

Analysis of the gene defect in large cohorts of patients with a diagnosis of heterozygous FH provided evidence that inherited defects in genes other than those encoding LDLR and APOB can cause the hypercholesterolemia typical of FH. In several of these cohorts, exhaustive analysis of the LDLR gene failed to reveal a defect in about 15% of the patients, and in 2 such studies a family with a sufficiently large pedigree was available to determine that an allele of these genes did not segregate with hypercholesterolemia, suggesting that their defect lay elsewhere (Sun et al., 1997; Haddad et al., 1999).

▼ Animal Model

Jones et al. (2007) examined the synthesis and catabolism of Vldl in mouse models of FH (Ldlr -/-) and ARH (Arh -/-). Despite similar rates of Vldl secretion in response to a high-sucrose diet, the rate of Vldl clearance was significantly higher in Arh-null mice than in Ldlr-null mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Hepatocytes from Arh-null mice but not Ldlr-null mice internalized beta-Vldl, demonstrating that ARH is not required for LDLR-dependent uptake of VLDL by the liver. Jones et al. (2007) concluded that the preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH.

Tags: 1p36.11