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

A

Pedigrees of the studied family. A child patient (Patient: IV.4) with elevated serum ALT, AST, and TBA levels and her nuclear family members (III.4, III.5, and IV.3) were evaluated by WGS analysis. Mutated alleles are depicted as “a” for SEMA7A. Square symbols: male; circles: female; solid: the patient. The reference alleles are depicted by a plus sign. The arrow points to the proband.

B

The homozygous p.R148W mutation in SEMA7A was further confirmed by Sanger sequencing.

C

The protein domain architecture of SEMA7A and conservation of the R148 position in Vertebrata.

D

Structures of WT SEMA7A and R148W mutant show local conformational changes, as a result of the replacement of an arginine (carbon atoms in yellow) with a tryptophan (pale) at position 148, which is highlighted in ball‐and‐stick models.

E, F

The surface electrostatic potential map of the WT and R148W mutant proteins, respectively, in which positively and negatively charged resides are expressed in blue and red, respectively, and non‐polar residues are denoted in white.

Figure 1. Identification of a new case with a rare homozygous p.R148W mutation in SEMA7A .