Human Genetics

, Volume 115, Issue 2, pp 139–148

A giant novel gene undergoing extensive alternative splicing is severed by a Cornelia de Lange-associated translocation breakpoint at 3q26.3

  • Emma T. Tonkin
  • Melanie Smith
  • Piet Eichhorn
  • Sandie Jones
  • Burhan Imamwerdi
  • Susan Lindsay
  • Mike Jackson
  • Tzu-Jou Wang
  • Maggie Ireland
  • John Burn
  • Ian D. Krantz
  • Philippa Carr
  • Tom Strachan
Original Investigation

DOI: 10.1007/s00439-004-1134-6

Cite this article as:
Tonkin, E.T., Smith, M., Eichhorn, P. et al. Hum Genet (2004) 115: 139. doi:10.1007/s00439-004-1134-6

Abstract

Cornelia de Lange syndrome (CdLS) is a rare developmental malformation syndrome characterised by mental handicap, growth retardation, distinctive facial features and limb reduction defects. The vast majority of CdLS cases are sporadic. We carried out a high density bacterial artificial chromosome (BAC) microarray comparative genome hybridisation screen but no evidence was found for a consistent pattern of microdeletion/microduplication. As an alternative, we focused on identifying chromosomal regions spanning associated translocation breakpoints. We prioritised the distal 3q region because of the occurrence, in a classical CdLS patient, of a de novo balanced translocation with a breakpoint at 3q26.3 and of reports of phenotypic overlap between cases of mild CdLS and individuals trisomic for the 3q26-q27 region. We show that the 3q26.3 breakpoint severs a previously uncharacterised giant gene, NAALADL2, containing at least 32 exons spanning 1.37 Mb. Northern blot analysis identified up to six different transcripts in the 1–10 kb range with strongest expression in kidney and placenta; embryonic expression was largely confined to duodenal and stomach endoderm, mesonephros, metanephros and pancreas. Transcript analysis identified extensive alternative splicing leading to multiple 5′ and 3′ untranslated regions and variable coding sequences. Multiple protein isoforms were defined by different N-terminal regions (with at least four alternative initiating methionine codons), and by differential protein truncation/use of alternative C-terminal sequences attributable to alternative splicing/polyadenylation. Outside the N-terminal regions, the predicted proteins showed significant homology to N-acetylated alpha-linked acidic dipeptidase and transferrin receptors. Mutation screening of NAALADL2 in a panel of CdLS patient DNA samples failed to identify patient-specific mutations. We discuss the possibility that the 3q26.3 translocation could nevertheless contribute to pathogenesis.

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Emma T. Tonkin
    • 1
  • Melanie Smith
    • 1
    • 4
  • Piet Eichhorn
    • 1
    • 5
  • Sandie Jones
    • 1
  • Burhan Imamwerdi
    • 1
  • Susan Lindsay
    • 1
  • Mike Jackson
    • 1
  • Tzu-Jou Wang
    • 1
  • Maggie Ireland
    • 1
    • 6
  • John Burn
    • 1
  • Ian D. Krantz
    • 2
  • Philippa Carr
    • 3
  • Tom Strachan
    • 1
  1. 1.Institute of Human Genetics, International Centre for LifeUniversity of NewcastleNewcastle upon TyneUK
  2. 2.Division of Human Genetics and Molecular BiologyThe Children’s Hospital of Philadelphia and the University of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Wellcome Trust Sanger InstituteHinxtonUK
  4. 4.Serono InternationalGeneva 20Switzerland
  5. 5.The Netherlands Cancer InstituteAntoni van Leeuwenhoek ZiekenhuisAmsterdamThe Netherlands
  6. 6.Postgraduate Institute for Medicine and DentistryUniversity of NewcastleNewcastle upon TyneUK