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. 2026 Jan;109(1):167-175.
doi: 10.1111/cge.70011. Epub 2025 Jun 29.

Expanding the Genetic and Phenotypic Spectrum of POLRMT-Related Mitochondrial Disease

Mahmoud R Fassad  1   2 , Sebastian Valenzuela  3 , Monika Oláhová  1   4 , Jack J Collier  1   5 , Charlotte V Y Knowles  6 , Eleni Mavraki  6 , Miriam Elbracht  7 , Nergis Güzel  7 , Thomas Herberhold  8 , Ingo Kurth  7 , Andrea Maier  9 , Larissa Mattern  7 , Carol Saunders  10   11   12 , Helen McCullagh  13 , Katrin Õunap  14 , Saskia B Wortmann  15 , Andre Reis  16 , Lei Zhang  10   11   12 , Claes M Gustafsson  3   17 , Robert McFarland  1   6 , Robert W Taylor  1   6
Affiliations

Expanding the Genetic and Phenotypic Spectrum of POLRMT-Related Mitochondrial Disease

Mahmoud R Fassad et al. Clin Genet. 2026 Jan.

Abstract

Mitochondrial diseases are a complex group of conditions exhibiting significant phenotypic and genetic heterogeneity. Genomic testing is increasingly used as the first step in the diagnostic pathway for mitochondrial diseases. We used next-generation sequencing followed by bioinformatic data analysis to identify potentially damaging variants in the POLRMT gene (NM_005035.4) in six new affected individuals. Structural protein analysis predicted the detrimental impact of variants on POLRMT protein structure. Patients show extended phenotypic abnormalities often presenting early in life with features including global developmental delay, cognitive impairment, short stature and muscular hypotonia. This study expands the genetic and phenotypic landscape of mitochondrial disease associated with POLRMT variants.

Keywords: POLRMT; mitochondrial disease; neurodevelopmental disorders; variant classification.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Family pedigrees, variant segregation and clinical characteristics of POLRMT patients. (a) Pedigrees of all 6 unrelated families reported in the current study show segregation of all reported variants within the available family members. (b) Clinical characteristics of patients with POLRMT variants reported in the current study and those previously reported by Oláhová et al. [3].
FIGURE 2
FIGURE 2
Sequence and structural analysis of mutations in POLRMT. (a) Multiple sequence alignment of POLRMT homologs; Homo sapiens (H.), Bacteriophage T7 (T7), Drosophila melanogaster (D.), Mus musculus (M.) and Gallus gallus (G.). The locations of the mutations are highlighted in yellow, and the prolines in two strongly conserved proline clusters are marked with bold text. (b) Structure of the transcription initiation complex bound to the light‐strand promoter (LSP) (PDB ID: 6ERP). The four main domains of POLRMT are the N‐terminal extension (yellow), the pentatricopeptide repeat (PPR) domain (blue), the N‐terminal domain (orange) and the C‐terminal domain (green). The locations of disease‐causing variants are shown (magenta) and highlighted with black circles. The active site is indicated as a full black circle. TFAM, TFB2M and the DNA substrate is coloured grey. (c, d) Images were generated from the transcription elongation complex (PDB ID: 5OLA) and the initiation complex (PDB ID: 6ERP). Residues implicated in disease are coloured magenta and interactions are shown with dashed lines. (c) P2, P3 and P5 harbours substitutions of residues in the proline‐rich regions at the core of POLRMT, close to the DNA/RNA hybrid and the active site. P6 harbours a variant at the position adjacent to the catalytic residue D922. (d) P1 harbours a substitution of E1056, which forms a salt bridge with R1059, to a lysine. P4 harbours the P294L and the G619S variants. In addition to the Q921E variant, P6 also harbours the D870N variant. D870 forms a salt bridge with R882.
See this image and copyright information in PMC

References

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