Biallelic <i>POLR3A</i> variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis

Rydning, Siri Lynne; Koht, Jeanette; Sheng, Ying; Sowa, Piotr; Hjorthaug, Hanne Sagsveen; Wedding, Iselin Marie; Erichsen, Anne Kjersti; Hovden, Inger Anette Hynås; Backe, Paul Hoff; Tallaksen, Chantal; Vigeland, Magnus Dehli; Selmer, Kaja Kristine

doi:10.1093/brain/awz041

Cited by 24 publications

(28 citation statements)

References 14 publications

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“…The c.1771-6C > G variant was also described in one patient said to have spastic ataxia but also with dystonia [10,11], without detailed MRI information. In a publication on atypical radiological findings in 4H leukodystrophy, one patient also carried this variant in heterozygous form, and, in retrospect, his last MRI showed small caudate and putamen with elevated T2 signal in addition to the signal abnormalities in the posterior limb of the internal capsule, fitting with his prominent extrapyramidal symptoms [9].…”

Section: Discussionmentioning

confidence: 99%

“…The c.1048 + 5G > T variant in a homozygous state has been described in a patient with Wiedemann-Rautenstrauch syndrome [16] and compound heterozygous with c.1771-7C > G in a patient classified as spastic ataxia [12]. The c.1771-7C > G variant has been found in patients classified as spastic ataxia, in combination with a frameshift variant [11,12]. The c.1771-6C > G variant has been described in patients in homozygous form with basal ganglia involvement [10].…”

Section: Genetic Findingsmentioning

confidence: 98%

“…During the last years, POLR3A variants without predominant ataxia have been reported: A striatal manifestation with predominant dystonia and MR involvement of putamen, caudate and red nucleus due to a homozygous founder variant in intron 13 was reported for three patients from two families with a Roma background [10]. In addition, biallelic POLR3A variants have been recognized as a cause of hereditary spastic ataxia [11,12].…”

Section: Introductionmentioning

confidence: 99%

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POLR3A variants with striatal involvement and extrapyramidal movement disorder

et al. 2020

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Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.

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Section: Discussionmentioning

confidence: 99%

Section: Genetic Findingsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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POLR3A variants with striatal involvement and extrapyramidal movement disorder

et al. 2020

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“…In addition to POLR3-related leukodystrophy, POLR1A has been associated with both acrofacial dysostosis 53 (MIM: 616462) and severe neurodegenerative disease with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy; 54 POLR3A is also, in addition to HLD7, associated with Wiedemann-Rautenstrauch syndrome, a neonatal progeroid syndrome 55 (MIM: 264090), and has been discussed as potential cause of hereditary ataxia and spastic paraparesis, 56,57 implying a broader phenotypic range for POLR3A mutations.…”

Section: Discussionmentioning

confidence: 99%

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

Haijes

Koster

Rehmann

et al. 2019

The American Journal of Human Genetics

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The RNA polymerase II complex (pol II) is responsible for transcription of all $21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly diseasecausing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

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“…Some HSP-related genes may be involved in other disorders in which spasticity is not among the main features, for example, FA2H (OMIM 611026) and KIAA1840 (OMIM 610844) mutations may cause neurodegeneration with brain-iron accumulation and Charcot-Marie-Tooth (CMT) (Kruer et al, 2010;Montecchiani et al, 2015). Similarly, genes that are involved 2 of 7 | ESTIAR ET Al. in other neurological disorders, such as ALS2 (OMIM 205100) and POLR3A (OMIM 614258), were also implicated in HSP (Eymard-Pierre et al, 2002;Rydning et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype

Estiar

Léveillé

Spiegelman

et al. 2020

Molec Gen & Gen Med

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Background Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor–Rakeb syndrome (KRS), have been recently implicated in HSP. Methods Whole‐exome sequencing was done in a Canada‐wide HSP cohort. Results Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2‐related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways. Conclusion Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.

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

Cited by 24 publications

References 14 publications

POLR3A variants with striatal involvement and extrapyramidal movement disorder

POLR3A variants with striatal involvement and extrapyramidal movement disorder

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype

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