Unique combination and in silico modeling of biallelic POLR3A variants as a cause of Wiedemann-Rautenstrauch syndrome

Abstract

Neonatal progeroid syndrome or Wiedemann-Rautenstrauch syndrome (WRS; MIM 264090) is a rare genetic disorder that has clinical symptoms including premature aging, lipodystrophy, and variable mental impairment. Until recently genetic background of the disease was unclear. However, recent studies have indicated that WRS patients have compound heterozygote variations in the POLR3A (RNA polymerase III subunit 3A; MIM 614258) gene that might be responsible for the disease phenotype. In this study we report a WRS patient that has compound heterozygote variations in the POLR3A gene. One of the reported variations in our patient, c.3568C>T, p.(Gln1190Ter), is a novel variation that was not reported before. The other variant, c.3337-11T>C, was previously shown in WRS patients in trans with other variations.

Fig. 1. Phenotypic view of our patient.

Black arrows indicate local lipoatrophies.

Fig. 2. Detected biallelic variants in the POLR3A gene.

The patient inherited the POLR3A c.[3337-11T>C] intronic splice site variant from her mother and POLR3A c.[3568C>T] p.(Gln1190Ter) variant from her father (P proband, F father, M mother).

Fig. 3. Protein homology modeling of hPOLR3A.

Protein sequence corresponding to NM_007055.3 mRNA sequence was used as the full-length human RNA polymerase III subunit A (hPOLR3_A) sequence. NM_007055.3:c.3568C>T introducing a stop codon after 1190th residue shown on the structure in black cartoon: Δ1190–1390. NG_029648.1(NM_007055.3):c.3337-11T>C causes skipping of exon 26. Position of exon 26 in C160 model is shown in magenta cartoon.

Fig. 4. Model of POLR3A (C160, shown in green cartoon) and its interacting partners in RNA polymerase III elongation complex. Each protein in the complex is shown with surface representation and different colors.

a Homology modeling analysis suggests that residues between 1190 and 1390 of POLR3A (inlet) interact with subunit C128, C17, and C25; residues translated from exon 26 (1112–1143) of POLR3A interact with C11 and C128. b Superimposing wild-type C160 (in green color) and C160Δ26 (in marine color) models suggest that exon skipping causes conformational changes in the region of C11 and C128 binding region of C160. Proteins interacting around the exon 26 of C160 is shown with surface representation.