A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis

Area of Science:

• Genetics
• Hepatology
• Molecular Biology

Background:

• Semaphorin 7A (SEMA7A) is a protein implicated in axon growth and other biological processes.
• Mutations in SEMA7A have been linked to vertebral fracture and Kallmann syndrome.
• The role of SEMA7A in liver function and cholestasis is not well understood.

Purpose of the Study:

• To investigate the genetic basis of familial cholestasis in a child with a novel SEMA7A mutation.
• To elucidate the mechanism by which the SEMA7A mutation leads to liver dysfunction.
• To evaluate the therapeutic efficacy of ursodeoxycholic acid and glutathione in this patient.

Main Methods:

• Whole-genome sequencing (WGS) was performed to identify causative mutations.
• A patient with familial cholestasis and elevated liver enzymes was studied.
• Sema7a^R145W homozygous mice were generated to model the human condition.
• Liver histology, LC-MS/MS, and Western blotting were used to assess liver function and transporter expression.

Main Results:

• A homozygous SEMA7A^R148W mutation was identified in the affected child.
• SEMA7A^R148W homozygous mice exhibited elevated serum ALT, AST, and total bile acid (TBA).
• Hepatocyte hydropic degeneration and increased liver bile acid (BA) levels were observed in mutant mice.
• The SEMA7A^R145W mutation reduced the expression of bile salt export pump (Bsep) and multidrug resistance-associated protein-2 (Mrp2).
• The child's liver function improved with ursodeoxycholic acid and glutathione treatment.

Conclusions:

• Homozygous SEMA7A^R145W mutation causes intrahepatic cholestasis.
• The mutation leads to cholestasis by reducing hepatic Bsep and Mrp2 expression.
• Targeted therapies can ameliorate liver dysfunction in patients with SEMA7A-associated cholestasis.