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

Lookup NU author(s): Dr Emma Tonkin, Pieter Eichhorn, Burhan Imamwerdi, Emerita Professor Susan Lindsay, Dr Michael Jackson, Dr Maggie Ireland, Professor Sir John BurnORCiD, Professor Tom Strachan


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Cornelia de Lange syndrome (CdLS) is a rare developmental malfortriation 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. © Springer-Verlag 2004.

Publication metadata

Author(s): Tonkin ET, Smith M, Eichhorn P, Jones S, Imamwerdi B, Lindsay S, Jackson M, Wang T-J, Ireland M, Burn J, Krantz ID, Carr P, Strachan T

Publication type: Article

Publication status: Published

Journal: Human Genetics

Year: 2004

Volume: 115

Issue: 2

Pages: 139-148

Print publication date: 01/07/2004

ISSN (print): 0340-6717

ISSN (electronic): 1432-1203

Publisher: Springer

URL: .htp://

DOI: 10.1007/s00439-004-1134-6

PubMed id: 15168106


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Funder referenceFunder name
G9826762Medical Research Council