neurogenetics

, Volume 14, Issue 3–4, pp 247–250

Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3

  • Ginevra Zanni
  • Chiara Scotton
  • Chiara Passarelli
  • Mingyan Fang
  • Sabina Barresi
  • Bruno Dallapiccola
  • Bin Wu
  • Francesca Gualandi
  • Alessandra Ferlini
  • E. Bertini
  • Wang Wei
Short Communication

Abstract

Whole exome sequencing in two-generational kindred from Bangladesh with early onset spasticity, mild intellectual disability, distal amyotrophy, and cerebellar atrophy transmitted as an autosomal recessive trait identified the following two missense mutations in the EXOSC3 gene: a novel p.V80F mutation and a known p.D132A change previously associated with mild variants of pontocerebellar hypoplasia type 1. This study confirms the involvement of RNA processing proteins in disorders with motor neuron and cerebellar degeneration overlapping with spinocerebellar ataxia 36 and rare forms of hereditary spastic paraplegia with cerebellar features.

Keywords

Exosome component 3 (EXOSC3) Hereditary spastic paraplegia (HSP) Pontocerebellar hypoplasia type 1 (PCH1) Spinocerebellar ataxia type 36 (SCA36) Whole exome sequencing (WES) 

Supplementary material

10048_2013_371_MOESM1_ESM.doc (40 kb)
Table S1Clinical features of the two affected siblings compared to D132A-related PCH1 patients (DOC 40 kb)

References

  1. 1.
    Wan J, Yourshaw M, Mamsa H, Rudnik-Schöneborn S, Menezes MP, Hong JE, Leong DW, Senderek J, Salman MS, Chitayat D, Seeman P, von Moers A, Graul-Neumann L, Kornberg AJ, Castro-Gago M, Sobrido MJ, Sanefuji M, Shieh PB, Salamon N, Kim RC, Vinters HV, Chen Z, Zerres K, Ryan MM, Nelson SF, Jen JC (2012) Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet 44(6):704–708PubMedCrossRefGoogle Scholar
  2. 2.
    Namavar Y, Barth PG, Poll-The BT, Baas F (2011) Classification, diagnosis, and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis 6:50PubMedCrossRefGoogle Scholar
  3. 3.
    Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, Graul-Neumann L, Seidel U, Korinthenberg R, Kirschner J, Seeger J, Ryan MM, Muntoni F, Steinlin M, Sztriha L, Colomer J, Hübner C, Brockmann K, Van Maldergem L, Schiff M, Holzinger A, Barth P, Reardon W, Yourshaw M, Nelson SF, Eggermann T, Zerres K (2013) Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology 80(5):438–446PubMedCrossRefGoogle Scholar
  4. 4.
    Liu Q, Greimann JC, Lima CD (2006) Reconstitution, activities, and structure of the eukaryotic RNA exosome. Cell 127(6):1223–1237PubMedCrossRefGoogle Scholar
  5. 5.
    Amblar M, Barbas A, Gomez-Puertas P, Arraiano CM (2007) The role of the S1 domain in exoribonucleolytic activity: substrate specificity and multimerization. RNA 13(3):317–327PubMedCrossRefGoogle Scholar
  6. 6.
    Finsterer J, Löscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G (2012) Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci 318(1–2):1–18PubMedCrossRefGoogle Scholar
  7. 7.
    Ikeda Y, Ohta Y, Kobayashi H, Okamoto M, Takamatsu K, Ota T, Manabe Y, Okamoto K, Koizumi A, Abe K (2012) Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement. Neurology 79(4):333–341PubMedCrossRefGoogle Scholar
  8. 8.
    Costello JL, Stead JA, Feigenbutz M, Jones RM, Mitchell P (2011) The C-terminal region of the exosome-associated protein Rrp47 is specifically required for box C/D small nucleolar RNA 3'-maturation. J Biol Chem 286(6):4535–4543PubMedCrossRefGoogle Scholar
  9. 9.
    Paciorkowski AR, Darras BT (2013) Making sense of genetic heterogeneity: emergence of pathways in developmental brain disorders. Neurology 80(5):426–427PubMedCrossRefGoogle Scholar
  10. 10.
    Hanada T, Weitzer S, Mair B, Bernreuther C, Wainger BJ, Ichida J, Hanada R, Orthofer M, Cronin SJ, Komnenovic V, Minis A, Sato F, Mimata H, Yoshimura A, Tamir I, Rainer J, Kofler R, Yaron A, Eggan KC, Woolf CJ, Glatzel M, Herbst R, Martinez J, Penninger JM (2013) CLP1 links tRNA metabolism to progressive motor-neuron loss. Nature 495(7442):474–480PubMedCrossRefGoogle Scholar
  11. 11.
    Lehner B, Sanderson CM (2004) A protein interaction framework for human mRNA degradation. Genome Res 14(7):1315–1323PubMedCrossRefGoogle Scholar
  12. 12.
    Yu Y, Wu BL, Wu J, Shen Y (2012) Exome and whole-genome sequencing as clinical tests: a transformative practice in molecular diagnostics. Clin Chem 58:1507–1509PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ginevra Zanni
    • 1
  • Chiara Scotton
    • 2
  • Chiara Passarelli
    • 2
    • 3
  • Mingyan Fang
    • 4
  • Sabina Barresi
    • 1
  • Bruno Dallapiccola
    • 3
  • Bin Wu
    • 4
  • Francesca Gualandi
    • 2
  • Alessandra Ferlini
    • 2
  • E. Bertini
    • 1
  • Wang Wei
    • 4
  1. 1.Department of NeurosciencesUnit of Molecular Medicine for Neuromuscular and Neurodegenerative disordersRomeItaly
  2. 2.Department of Medical SciencesUniversity of FerraraFerraraItaly
  3. 3.Bambino Gesù Children’s Hospital, IRCCSRomeItaly
  4. 4.BGI-ShenzhenShenzhenChina

Personalised recommendations