SLC10A1 – Familial Hypercholanemia

Biallelic variants in SLC10A1 cause familial hypercholanemia type 2, an autosomal recessive disorder characterized by impaired hepatocellular uptake of conjugated bile salts and persistent hypercholanemia with minimal cholestatic injury. Patients often present with markedly elevated plasma bile acids but variable clinical signs ranging from asymptomatic to transient jaundice, motor and growth delays.

Extensive genetic evidence supports a definitive association: at least 33 unrelated probands carrying homozygous or compound heterozygous SLC10A1 variants have been described across 7 families (PMID:31574858). Segregation analysis in multiple pedigrees confirms autosomal recessive inheritance, with 8 additional affected relatives demonstrating co-segregation of SLC10A1 alleles. Identified pathogenic variants include c.755G>A (p.Arg252His), c.800C>T (p.Ser267Phe), c.263T>C (p.Ile88Thr), c.595A>C (p.Ser199Arg) and c.812A>G (p.Asn271Ser).

The variant spectrum comprises five missense changes affecting conserved residues in NTCP’s transmembrane and extracellular loops. The recurrent p.Ser267Phe allele has been observed in over 20 probands of Asian descent, with allele frequencies up to 4.7% in controls, indicating a founder effect in East Asian populations. Novel missense substitutions p.Ile88Thr and p.Ser199Arg each co-segregate with hypercholanemia in compound heterozygous individuals and have not been reported in population databases (PMID:29290974; PMID:31661128).

Functional assays demonstrate markedly reduced taurocholate uptake for all pathogenic variants. The p.Arg252His change abolishes NTCP membrane localization and bile salt transport in oocytes (PMID:24867799). NTCP global knockout mice recapitulate human hypercholanemia and reveal compensatory auxiliary transporters sustaining enterohepatic cycling (PMID:35937832). Rescue experiments in HEK293 cells confirm loss-of-function as the primary mechanism.

Clinically, affected infants may exhibit indirect hyperbilirubinemia and delayed motor milestones (HP:0001270), growth retardation (HP:0001510) or transient cholestatic jaundice that resolves, whereas adults homozygous for p.Ser267Phe often remain asymptomatic aside from elevated bile acids. Long-term follow-up reveals associated vitamin D deficiency and osteopenia, underscoring extracorporeal sequelae of chronic hypercholanemia.

No significant conflicting evidence has been reported; all studies consistently implicate SLC10A1 LOF in familial hypercholanemia type 2. While modifier genes may influence phenotypic variability, no alternative molecular etiology has been identified in affected individuals.

In summary, definitive genetic and functional data establish autosomal recessive SLC10A1 deficiency as causative for familial hypercholanemia type 2. Genetic testing for known NTCP variants enables accurate diagnosis, informs prognosis, and guides monitoring of bile acids and bone health. Clinically actionable insights include surveillance of vitamin D levels and bone density in homozygous individuals.

References

• Hepatology (Baltimore, Md.) • 2015 • Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. PMID:24867799
• Oncotarget • 2017 • Sodium taurocholate cotransporting polypeptide (NTCP) deficiency: Identification of a novel SLC10A1 mutation in two unrelated infants presenting with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia. PMID:29290974
• Molecular Medicine Reports • 2019 • Clinical and molecular characterization of four patients with NTCP deficiency from two unrelated families harboring the novel SLC10A1 variant c.595A>C (p.Ser199Arg). PMID:31661128
• Medicine • 2019 • Clinical and histopathologic features of sodium taurocholate cotransporting polypeptide deficiency in pediatric patients. PMID:31574858
• Frontiers in Endocrinology • 2022 • NTCP Deficiency Affects the Levels of Circulating Bile Acids and Induces Osteoporosis. PMID:35937832

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