ClinVar

Familial Hypercholanemia 2

In a 30-month-old Chinese boy with familial hypercholanemia-2 (FHCA2; 619256), Deng et al. (2016) identified a homozygous c.800C-T transition in the SLC10A1 gene, resulting in a ser267-to-phe (S267F) substitution. The variant, which was confirmed by Sanger sequencing, segregated with the phenotype in the family. The S267F variant was considered to be a polymorphism, as it was found at an allele frequency of 4.7% in healthy Chinese controls. One homozygote identified in the controls was a 30-year-old woman who was asymptomatic and had mildly elevated serum total bile acids. These findings were consistent with other studies demonstrating that this polymorphism is common in East Asian countries, including China and Vietnam, but not in European, African, or Hispanic countries. Deng et al. (2016) noted that SLC10A1 is the functional receptor of human hepatitis viruses B and D and that the S267F mutation impairs HBV infections in culture; this variant allele is associated with resistance to chronic hepatitis B in humans. The high allele frequency in this population may be a result of positive selection, since hepatitis B is more prevalent in those regions.

In 2 unrelated Chinese infants with FHCA2 and neonatal hyperbilirubinemia, Qiu et al. (2017) identified compound heterozygous variants in the SLC10A1 gene: S267F and a c.263T-C transition, resulting in an ile88-to-thr substitution (I88T; 182396.0003) at a conserved residue. The variants, which were found by Sanger sequencing, segregated with the disorder in both families. I88T was not present in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, but was found in 1 of 150 healthy Chinese controls (allele frequency of 0.67%). Functional studies of the I88T variant were not performed, but molecular modeling suggested that it may alter the conformation of the molecule.

Liu et al. (2017) identified 8 Chinese individuals with FHCA2 associated with a homozygous S267F variant in the SLC10A1 gene. Li et al. (2018) also described a Chinese boy with FHCA2 who carried the S267F variant in homozygosity.

Resistance to Hepatitis B Virus

Among 1,899 Chinese Han patients with chronic hepatitis B infection (see 610424) and 1,828 controls, Peng et al. (2015) found that the S267F variant in the SLC10A1 gene was significantly associated with resistance to chronic hepatitis B. The S267F variant was associated with healthy status irrespective of hepatitis surface B antibody status (p = 5.7 x 10(-23), odds ratio of 0.36), and was associated with lower incidence of acute liver failure (p = 0.007). Structural modeling showed that the S267F variant may interfere with ligand binding, thereby preventing HBV from cellular entry. The findings supported the role of SLC10A1 as a cellular receptor for HBV, and suggested that the S267F polymorphism confers a protective effect in HBV infection.

Variant Function

In vitro functional expression studies by Ho et al. (2004) showed that the S267F variant had a 98% reduction in taurocholate transport activity compared to wildtype, almost a complete loss of function. The variant showed normal expression at the plasma membrane and also retained transported activity for estrone sulfate. These findings pointed to S267 as a critical position for bile acid binding or recognition. The study also suggested that functionally relevant polymorphisms in SLC10A1 may have an impact on bile acid homeostasis.