Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy

Abstract

Mutations in POLR3A encoding the largest subunit of RNA polymerase III (Pol III) were found to be responsible for the majority of cases presenting with three clinically overlapping hypomyelinating leukodystrophy phenotypes. We uncovered in three cases without POLR3A mutation recessive mutations in POLR3B, which codes for the second largest subunit of Pol III. Mutations in genes coding for Pol III subunits are a major cause of childhood-onset hypomyelinating leukodystrophies with prominent cerebellar dysfunction, oligodontia, and hypogonadotropic hypogonadism.

Figure 1

POLR3B Mutations (A) Genomic sequence chromatograms and amino acid conservation across species is shown for all missense and nonsense POLR3B mutations. Individual 1 is compound heterozygote for mutations c.1508C>A and c.1568T>A; individual 2 is compound heterozygote for mutations c.1533delT and c.1568T>A, and individual 3 is compound heterozygote for mutations c.1568T>A and c.2686A>T. The amino acid conservation across species is shown for all mutations. The following abbreviations are used: D. melanogaster, Drosophila melanogaster; D. rerio, Danio rerio; H. sapiens, Homo sapiens; M. musculus, Mus musculus; S. cerevisiae, Saccharomyces cerevisiae. (B) 3D representations of POLR3B missense, deletion (frameshift), and nonsense mutations. Point mutations identified in POLR3B are displayed according to their equivalent positions in the yeast RNA Polymerase II RPB2 subunit. Numbers in brackets refer to the positions in yeast RPB2. Images have been generated with PyMol software (Schrödinger). RPB1 is shown in blue, RPB2 in green, RPB7 in brown, RPB4 in pink, RPB8 in orange, and RPB11 in magenta.

Figure 2

Teeth Abnormalities (A and B) The teeth abnormalities seen in individual 1: unspecified age at tooth eruption and the absence of permanent mandibular second premolars with abnormal shape of the permanent maxillary central and lateral incisors. (C and D) The teeth abnormalities of individual 2: delayed tooth eruption with complete retention of the primary maxillary central incisors and the mandibular lateral incisors.

Figure 3

MRI Characteristics (A, D, and G) Sagittal T1-weighted images of the brain for individuals 1 (A), 2 (D), and 3 (G) at the level of the midline demonstrating the thin corpus callosum and vermian cerebellar atrophy (thick white arrows). (B, E, and H) Axial T2-weighted images of the brain for individuals 1 (B), 2 (E), and 3 (H) at the level of the pons and the dentate nucleus demonstrating a mild T2 hyperintensity of the cerebellar white matter associated with the typical hypointensity of the dentate nucleus (small white arrows).¹⁹ (C, F, and I) Axial T2-weighted images of the brain for individuals 1 (C), 2 (F), and 3 (I) at the level of the basal ganglia showing the mild hyperintense white matter characteristic of hypomyelination; there is relative sparing of the optic radiations and anterolateral nucleus of the thalamus (small black arrows), which appear hypointense.