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Comment
. 2019 Apr 1;142(4):e12.
doi: 10.1093/brain/awz041.

Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis

Siri L Rydning  1   2 , Jeanette Koht  1   3 , Ying Sheng  4 , Piotr Sowa  5 , Hanne S Hjorthaug  4 , Iselin M Wedding  2 , Anne Kjersti Erichsen  6 , Inger Anette Hovden  7 , Paul H Backe  8   9 , Chantal M E Tallaksen  2 , Magnus D Vigeland  1   4 , Kaja K Selmer  10   11
Affiliations
Comment

Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis

Siri L Rydning et al. Brain. .
No abstract available

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Figures

Figure 1
Figure 1
Pedigrees, MRIs and sequencing chromatograms. (A) Pedigrees of the 10 families showing co-segregation of the variants and disease. In Families F1–F6 in trans status was confirmed by mRNA analyses, and in Families F7-F10 by sequencing of family members. In Family 7, the parents were not available for analyses, hence adult children were sequenced and found to carry only one of the variants each (results not included in the pedigree due to anonymity restrictions). Asterisks indicate that whole exome sequencing was performed. (B) MRI of the brain. (i–iv) The superior cerebellar peduncles of Patient F2–1 showing hyperintense signal in FLAIR MRI in coronal (i), sagittal (ii) and axial (iii) views, and isointense signal in T1-weighted coronal images (iv). Arrows indicate the superior cerebellar peduncles. (v) Coronal T1-weighted image of Patient F7–1 showing mild atrophy of the cerebellar vermis (midline) and hemispheres. (vi) Axial FLAIR image of Patient F8–1 showing hyperintense signal in the corticospinal tracts at the level of the posterior limb of the internal capsule (arrows). The MRI signal in all images was assessed in relation to the reference area in the caudate nucleus (Vrij-van den Bos et al., 2017). (C) Analysis of NMD of the c.3655G>T variant. Messenger RNA from lymphocytes cultured with and without inhibitor of NMD was reverse transcribed and amplified by PCR, followed by Sanger sequencing (details in the Supplementary material). The figure shows sequencing chromatograms of Patients F1–2 and F2–1. These patients carry the c.3655 G>T and c.1909+22G>A variants in trans, with the latter previously shown to result in a leaky splice site and partial NMD. The c.3655 position is marked by an arrow in the centre of each graph. [C(i and ii)] Chromatograms from analysis of Patient F1–2 without and with NMD inhibitor, respectively. [C(iii and iv)] Chromatograms from analysis of Patient F2–1 without and with NMD inhibitor, respectively. Notably, addition of NMD inhibitor led to increased amounts of product from the c.3655T allele as compared to the c.3655G allele. This result is consistent with complete NMD of the c.3655G>T variant, and partial degradation of transcripts from the c.1909+22G>A variant.
See this image and copyright information in PMC

Comment in

Comment on

  • Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.
    Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmüller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brüstle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schöls L, Nürnberg P, Zuchner S, Klockgether T, Ramirez A, Schüle R. Minnerop M, et al. Brain. 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095. Brain. 2017. PMID: 28459997 Free PMC article.

References

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    1. Minnerop M, Kurzwelly D, Rattay TW, Timmann D, Hengel H, Synofzik M, et al.Reply: POLR3A variants in hereditary spastic paraplegia and ataxia. Brain 2018; 141: e2. - PMC - PubMed

Supplementary concepts