A New Case of Autosomal-Dominant POLR3B-Related Disorder: Widening Genotypic and Phenotypic Spectrum

Abstract

POLR3B encodes the RPC2 subunit of RNA polymerase III. Pathogenic variants are associated with biallelic hypomyelinating leukodystrophy belonging to the POLR-related disorders. Recently, the association with dominant demyelinating neuropathy, classified as Charcot-Marie-Tooth syndrome type 1I (CMT1I), has been reported as well. Here we report on an additional patient presenting with developmental delay and generalized epilepsy, followed by the onset of mild pyramidal and cerebellar signs, vertical gaze palsy and subclinical demyelinating polyneuropathy. A new heterozygous de novo missense variant, c.1297C > G, p.Arg433Gly, in POLR3B was disclosed via trio-exome sequencing. In silico analysis confirms the hypothesis on the variant pathogenicity. Our research broadens both the genotypic and phenotypic spectrum of the autosomal-dominant POLR3B-related condition.

Keywords: POLR3A; ataxia; heterozygous; leukodystrophy; neuropathy; spinocerebellar; vertical gaze palsy.

Figure 1

3T brain MRI ((A): sagittal T1-weighted image; (B): coronal T2-weighted image): cerebellar vermis appears of reduced volume (A,B); mild increase in the interfolial spaces can be noticed in the superior vermis and in the cerebellar hemispheres (B). No evidence of supra—(not shown) or sub-tentorial white matter involvement (B).

Figure 2

In silico structural prediction analysis: (A) domain representation of the DNA-directed RNA polymerase III subunit RPC2 with known POLR3B-dominant negative de novo missense variants (in red the one described in this report, Arg433Gly), generated by IBS 2.0. (B) Alphafold monomer v2.0 prediction for DNA-directed RNA polymerase III subunit RPC2 (ConSurf server). (C) RPC2 amino acid sequence generated by ConSurf server. The Arg433 residue is indicated with black arrow in both figures. (D,E) Disruption of the interaction network of Arg433 residue (wild-type) caused by substitution with Gly433 (mutant).