Novel <i>POLR1C</i> mutation in RNA polymerase III‐related leukodystrophy with severe myoclonus and dystonia

Kraoua, Ichraf; Karkar, Adnane; Drissi, C.; Benrhouma, Hanène; Klaa, Hédia; Samaan, Simon; Renaldo, Florence; Elmaleh, Monique; Hamouda, M. Ben; Abdelhak, Sonia; Boespflug‐Tanguy, Odile; Youssef-Turki, Ilfghem Ben; Dorboz, Imen

doi:10.1002/mgg3.914

Cited by 12 publications

(11 citation statements)

References 5 publications

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“…Here, we propose exome, transcriptome and metabolome studies to aid in the diagnosis and molecular elucidation of a child presenting with chronic progressive cerebellar ataxia and an undiagnosed condition. Altogether, the results obtained reinforce the association between POLR1C mutations and hypomyelinating leukodystrophy [ 19 , 20 , 21 , 22 ] as well as the importance of multi-omics approaches to disease.…”

Section: Introductionsupporting

confidence: 72%

“…An in silico pathogenicity assessment performed with PolyPhen-2 [ 25 ] and SIFT [ 24 ] predicted these variants to be deleterious (pathogenic or likely pathogenic). Both missense variants found at POLR1C —a gene that encodes a subunit common to RNA polymerases I (POLR1) and III (POLR3)—affect amino acids that are conserved through species, and have been known to be associated with Treacher Collins syndrome (TCS) [ 31 ] and hypomyelinating leukodystrophies [ 19 , 20 , 21 , 22 ]. Furthermore, the variant found at MMACHC predicts a change of the arginine residue at position 91 to lysine resulting in a frameshift and a premature stop codon.…”

Section: Resultsmentioning

confidence: 99%

“…We reported on a Spanish patient with POLR1C hypomyelinating leukodystrophy. Leukodystrophy due to POLR1C mutation is exceptionally rare; so far, only 26 such patients have been reported worldwide [ 19 , 20 , 21 , 22 ]. Demographic, genetic, clinical, and radiological characteristics of our patient and those of all published cases are summarized in Table 1 , Table 2 and Table 3 .…”

Section: Discussionmentioning

confidence: 99%

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Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia

Ching-López

Martínez-González

Arrabal

et al. 2021

IJMS

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Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

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Section: Introductionsupporting

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia

Ching-López

Martínez-González

Arrabal

et al. 2021

IJMS

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“…5,6 Here we have expanded the clinical and genetic spectrum of POLR3-related leukodystrophy caused by POLR1C mutations. 1,7 Integrating clinical features such as myopia, characteristic MRI patterns, and next-generation sequencing will facilitate the making of definitive diagnoses in unresolved atypical cases with hypomyelination and ataxia.…”

Section: Jcnmentioning

confidence: 99%

A Familial Case of Childhood Ataxia with Leukodystrophy Due to Novel POLR1C Mutations

et al. 2020

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Dear Editor, Of the 17 subunits of RNA polymerase III (POLR3), POLR3A and POLR3B are the largest and second largest, respectively, which together form the catalytic core of the polymerase. Most cases of POLR3-related leukodystrophy are caused by mutations in POLR3A or POL-R3B, with POLR1C mutations causing about 5% of cases. 1 Distinctively, POLR1C is a shared subunit of both RNA polymerase I (POLR1) and POLR3, and molecular defects selectively modify the availabilities of these enzymes, leading to two distinct clinical conditions: Treacher Collins syndrome with autosomal recessive inheritance, and POLR3-related leukodystrophy. 1 Only 20 POLR1C mutations presenting with the spectrum of POLR3-related leukodystrophy have been reported worldwide. Here we report two Korean siblings with ataxia and leukodystrophy caused by novel POLR1C mutations. A 5-year-old girl visited our clinic with an ataxic gait. She showed tremor and clumsiness affecting her hands, and mild dysarthria. An ocular examination revealed myopia with mild optic nerve atrophy. Neurocognitive profiles revealed mild mental retardation with an intelligence quotient of 65. Brain MRI showed diffuse hypomyelination, except for T2-weighted hypointensities in the ventrolateral thalamus and optic radiation, without cerebellar atrophy (Fig. 1A, B, and C). She underwent menarche at 13 years of age, without evidence of hypogonadotropic hypogonadism. No dental or skeletal abnormalities were found. Her ataxia, tremor, and dysarthria were worsening at her current age of 15 years. She scored 28/40 on the Scale for the Assessment and Rating of Ataxia (SARA). The younger brother of the proband also showed slow progressive ataxia, tremor, and dysarthria from 5 years of age with similar MRI findings (Fig. 1D, E, and F). He had difficulty walking, with ataxia and myoclonus (Supplementary Video 1 in the online-only Data Supplement). Myopia with mild optic nerve atrophy was also noted. No dental or endocrine abnormalities have been found at his current age of 12 years. He had a SARA score of 13/40. Neither sibling exhibited spasticity, dystonia, or seizures. Because of the extreme genetic heterogeneity of leukodystrophy and ataxia, we performed whole-exome sequencing and analyzed the candidate genes causing hypomyelination and ataxia, including POLR3A, POLR3B, PLP1, GJC2, and TUBB4A, which did not reveal any pathogenic variants in them. We identified compound heterozygous POLR1C mutations: a frameshift mutation (c.698_699insAA: p.Tyr233fs) and a missense mutation (c.713A>G: p.Asp238Gly) validated with Sanger sequencing (Fig. 1G). The identified variants were classified as pathogenic based on the 2015 guidelines of the American College of Medical Genetics and Genomics, with evidence levels of PVS1, PM2, and PM3 for p.Tyr233fs, and PS3, PM1, PM2, PM3, and PP4 for p.Asp238Gly. 2 POLR3 synthetizes small noncoding RNAs that play essential roles in cells, including transcription, and RNA processing and translation. 3 Therefore, members of the POLR3 family are considered housekee...

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“… 10 Previously reported 32 cases with POLR1C variants presented with at least one of these features. 6 , 11 , 12 Thus, the present case also suggested that lacking characteristic features of Pol III–related leukodystrophy does not exclude the presence of POLR1C variants.…”

Section: Discussionmentioning

confidence: 51%

POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy

Kashiki

Miyamoto

et al. 2020

Neurol Genet

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ObjectiveTo further clarify the molecular pathogenesis of RNA polymerase III (Pol III)-related leukodystrophy caused by biallelic POLR1C variants at a cellular level and potential effects on its downstream genes.MethodsExome analysis and molecular functional studies using cell expression and long-read sequencing analyses were performed on 1 family with hypomyelinating leukodystrophy showing no clinical and MRI findings characteristic of Pol III–related leukodystrophy other than hypomyelination.ResultsBiallelic novel POLR1C alterations, c.167T>A, p.M56K and c.595A>T, p.I199F, were identified as causal variants. Functional analyses showed that these variants not only resulted in altered protein subcellular localization and decreased protein expression but also caused abnormal inclusion of introns in 85% of the POLR1C transcripts in patient cells. Unexpectedly, allelic segregation analysis in each carrier parent revealed that each heterozygous variant also caused the inclusion of introns on both mutant and wild-type alleles. These findings suggest that the abnormal splicing is not direct consequences of the variants, but rather reflect the downstream effect of the variants in dysregulating splicing of POLR1C, and potentially other target genes.ConclusionsThe lack of characteristic clinical findings in this family confirmed the broad clinical spectrum of Pol III–related leukodystrophy. Molecular studies suggested that dysregulation of splicing is the potential downstream pathomechanism for POLR1C variants.

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Novel POLR1C mutation in RNA polymerase III‐related leukodystrophy with severe myoclonus and dystonia

Cited by 12 publications

References 5 publications

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia

A Familial Case of Childhood Ataxia with Leukodystrophy Due to Novel POLR1C Mutations

POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy

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