Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia

Martina Minnerop, Delia Kurzwelly, Holger Wagner, Anne S. Soehn, Jennifer Reichbauer, Feifei Tao, Tim W. Rattay, Michael Peitz, Kristina Rehbach, Alejandro Giorgetti, Angela Pyle, Holger Thiele, Janine Altmüller, Dagmar Timmann, Ilker Karaca, Martina Lennarz, Jonathan Baets, Holger Hengel, Matthis Synofzik, Burcu Atasu & 36 others Shawna Feely, Marina Kennerson, Claudia Stendel, Tobias Lindig, Michael A. Gonzalez, Rudiger Stirnberg, Marc Sturm, Sandra Roeske, Johanna Jung, Peter Bauer, Ebba Lohmann, Stefan Herms, Stefanie Heilmann-Heimbach, Garth Nicholson, Muhammad Mahanjah, Rajech Sharkia, Paolo Carloni, Oliver Brüstle, Thomas Klopstock, Katherine D. Mathews, Michael E. Shy, Peter De Jonghe, Patrick F. Chinnery, Rita Horvath, Jürgen Kohlhase, Ina Schmitt, Michael Wolf, Susanne Greschus, Katrin Amunts, Wolfgang Maier, Ludger Schöls, Peter Nürnberg, Stephan L Zuchner, Thomas Klockgether, Alfredo Ramirez, Rebecca Schüle

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in 3.1% of index cases. Interestingly, 480% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909 + 22G4A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909 + 22G4A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909 + 22G4A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 104). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Original languageEnglish (US)
Pages (from-to)1561-1578
Number of pages18
JournalBrain
Volume140
Issue number6
DOIs
StatePublished - 2017

Fingerprint

Mutation
Hereditary Spastic Paraplegia
Cerebellar Ataxia
Phenotype
Anodontia
Spinocerebellar Degenerations
Genes
Exome
Spastic Ataxia
RNA Splice Sites
Movement Disorders
Periodontal Diseases
Tremor
Human Genome
Rare Diseases
Introns
Tooth
Magnetic Resonance Imaging
DNA

Keywords

  • Cerebellar ataxia
  • Hereditary spastic paraplegia
  • Leukodystrophy
  • POLR3A
  • Spastic ataxia

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Minnerop, M., Kurzwelly, D., Wagner, H., Soehn, A. S., Reichbauer, J., Tao, F., ... Schüle, R. (2017). Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain, 140(6), 1561-1578. https://doi.org/10.1093/brain/awx095

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. / Minnerop, Martina; Kurzwelly, Delia; Wagner, Holger; Soehn, Anne S.; Reichbauer, Jennifer; Tao, Feifei; Rattay, Tim W.; Peitz, Michael; Rehbach, Kristina; Giorgetti, Alejandro; Pyle, Angela; Thiele, Holger; Altmüller, Janine; Timmann, Dagmar; Karaca, Ilker; Lennarz, Martina; Baets, Jonathan; Hengel, Holger; Synofzik, Matthis; Atasu, Burcu; Feely, Shawna; Kennerson, Marina; Stendel, Claudia; Lindig, Tobias; Gonzalez, Michael A.; Stirnberg, Rudiger; Sturm, Marc; Roeske, Sandra; Jung, Johanna; Bauer, Peter; Lohmann, Ebba; Herms, Stefan; Heilmann-Heimbach, Stefanie; Nicholson, Garth; Mahanjah, Muhammad; Sharkia, Rajech; Carloni, Paolo; Brüstle, Oliver; Klopstock, Thomas; Mathews, Katherine D.; Shy, Michael E.; De Jonghe, Peter; Chinnery, Patrick F.; Horvath, Rita; Kohlhase, Jürgen; Schmitt, Ina; Wolf, Michael; Greschus, Susanne; Amunts, Katrin; Maier, Wolfgang; Schöls, Ludger; Nürnberg, Peter; Zuchner, Stephan L; Klockgether, Thomas; Ramirez, Alfredo; Schüle, Rebecca.

In: Brain, Vol. 140, No. 6, 2017, p. 1561-1578.

Research output: Contribution to journalArticle

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, SL, Klockgether, T, Ramirez, A & Schüle, R 2017, 'Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia', Brain, vol. 140, no. 6, pp. 1561-1578. https://doi.org/10.1093/brain/awx095
Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F et al. Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain. 2017;140(6):1561-1578. https://doi.org/10.1093/brain/awx095
Minnerop, Martina ; Kurzwelly, Delia ; Wagner, Holger ; Soehn, Anne S. ; Reichbauer, Jennifer ; Tao, Feifei ; Rattay, Tim W. ; Peitz, Michael ; Rehbach, Kristina ; Giorgetti, Alejandro ; Pyle, Angela ; Thiele, Holger ; Altmüller, Janine ; Timmann, Dagmar ; Karaca, Ilker ; Lennarz, Martina ; Baets, Jonathan ; Hengel, Holger ; Synofzik, Matthis ; Atasu, Burcu ; Feely, Shawna ; Kennerson, Marina ; Stendel, Claudia ; Lindig, Tobias ; Gonzalez, Michael A. ; Stirnberg, Rudiger ; Sturm, Marc ; Roeske, Sandra ; Jung, Johanna ; Bauer, Peter ; Lohmann, Ebba ; Herms, Stefan ; Heilmann-Heimbach, Stefanie ; Nicholson, Garth ; Mahanjah, Muhammad ; Sharkia, Rajech ; Carloni, Paolo ; Brüstle, Oliver ; Klopstock, Thomas ; Mathews, Katherine D. ; Shy, Michael E. ; De Jonghe, Peter ; Chinnery, Patrick F. ; Horvath, Rita ; Kohlhase, Jürgen ; Schmitt, Ina ; Wolf, Michael ; Greschus, Susanne ; Amunts, Katrin ; Maier, Wolfgang ; Schöls, Ludger ; Nürnberg, Peter ; Zuchner, Stephan L ; Klockgether, Thomas ; Ramirez, Alfredo ; Schüle, Rebecca. / Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. In: Brain. 2017 ; Vol. 140, No. 6. pp. 1561-1578.
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title = "Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia",
abstract = "Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in 3.1{\%} of index cases. Interestingly, 480{\%} of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909 + 22G4A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909 + 22G4A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909 + 22G4A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 104). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3{\%} of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.",
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author = "Martina Minnerop and Delia Kurzwelly and Holger Wagner and Soehn, {Anne S.} and Jennifer Reichbauer and Feifei Tao and Rattay, {Tim W.} and Michael Peitz and Kristina Rehbach and Alejandro Giorgetti and Angela Pyle and Holger Thiele and Janine Altm{\"u}ller and Dagmar Timmann and Ilker Karaca and Martina Lennarz and Jonathan Baets and Holger Hengel and Matthis Synofzik and Burcu Atasu and Shawna Feely and Marina Kennerson and Claudia Stendel and Tobias Lindig and Gonzalez, {Michael A.} and Rudiger Stirnberg and Marc Sturm and Sandra Roeske and Johanna Jung and Peter Bauer and Ebba Lohmann and Stefan Herms and Stefanie Heilmann-Heimbach and Garth Nicholson and Muhammad Mahanjah and Rajech Sharkia and Paolo Carloni and Oliver Br{\"u}stle and Thomas Klopstock and Mathews, {Katherine D.} and Shy, {Michael E.} and {De Jonghe}, Peter and Chinnery, {Patrick F.} and Rita Horvath and J{\"u}rgen Kohlhase and Ina Schmitt and Michael Wolf and Susanne Greschus and Katrin Amunts and Wolfgang Maier and Ludger Sch{\"o}ls and Peter N{\"u}rnberg and Zuchner, {Stephan L} and Thomas Klockgether and Alfredo Ramirez and Rebecca Sch{\"u}le",
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TY - JOUR

T1 - Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia

AU - Minnerop, Martina

AU - Kurzwelly, Delia

AU - Wagner, Holger

AU - Soehn, Anne S.

AU - Reichbauer, Jennifer

AU - Tao, Feifei

AU - Rattay, Tim W.

AU - Peitz, Michael

AU - Rehbach, Kristina

AU - Giorgetti, Alejandro

AU - Pyle, Angela

AU - Thiele, Holger

AU - Altmüller, Janine

AU - Timmann, Dagmar

AU - Karaca, Ilker

AU - Lennarz, Martina

AU - Baets, Jonathan

AU - Hengel, Holger

AU - Synofzik, Matthis

AU - Atasu, Burcu

AU - Feely, Shawna

AU - Kennerson, Marina

AU - Stendel, Claudia

AU - Lindig, Tobias

AU - Gonzalez, Michael A.

AU - Stirnberg, Rudiger

AU - Sturm, Marc

AU - Roeske, Sandra

AU - Jung, Johanna

AU - Bauer, Peter

AU - Lohmann, Ebba

AU - Herms, Stefan

AU - Heilmann-Heimbach, Stefanie

AU - Nicholson, Garth

AU - Mahanjah, Muhammad

AU - Sharkia, Rajech

AU - Carloni, Paolo

AU - Brüstle, Oliver

AU - Klopstock, Thomas

AU - Mathews, Katherine D.

AU - Shy, Michael E.

AU - De Jonghe, Peter

AU - Chinnery, Patrick F.

AU - Horvath, Rita

AU - Kohlhase, Jürgen

AU - Schmitt, Ina

AU - Wolf, Michael

AU - Greschus, Susanne

AU - Amunts, Katrin

AU - Maier, Wolfgang

AU - Schöls, Ludger

AU - Nürnberg, Peter

AU - Zuchner, Stephan L

AU - Klockgether, Thomas

AU - Ramirez, Alfredo

AU - Schüle, Rebecca

PY - 2017

Y1 - 2017

N2 - Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in 3.1% of index cases. Interestingly, 480% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909 + 22G4A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909 + 22G4A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909 + 22G4A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 104). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

AB - Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in 3.1% of index cases. Interestingly, 480% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909 + 22G4A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909 + 22G4A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909 + 22G4A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 104). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

KW - Cerebellar ataxia

KW - Hereditary spastic paraplegia

KW - Leukodystrophy

KW - POLR3A

KW - Spastic ataxia

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