Human Genetics

, Volume 120, Issue 1, pp 1–21 | Cite as

A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes I: general principles and overview

  • Jian-Min ChenEmail author
  • Claude Férec
  • David N. Cooper


The 3′ regulatory regions (3′ RRs) of human genes play an important role in regulating mRNA 3′ end formation, stability/degradation, nuclear export, subcellular localization and translation and are consequently rich in regulatory elements. Although 3′ RRs contain only ∼0.2% of known disease-associated mutations, this is likely to represent a rather conservative estimate of their actual prevalence. In an attempt to catalogue 3′ RR-mediated disease and also to gain a greater understanding of the functional role of regulatory elements within 3′ RRs, we have performed a systematic analysis of disease-associated 3′ RR variants; 121 3′ RR variants in 94 human genes were collated. These included 17 mutations in the upstream core polyadenylation signal sequence (UCPAS), 81 in the upstream sequence (USS) between the translational termination codon and the UCPAS, 6 in the left arm of the ‘spacer’ sequence (LAS) between the UCPAS and the pre-mRNA cleavage site (CS), 3 in the right arm of the ‘spacer’ sequence (RAS) or downstream core polyadenylation signal sequence (DCPAS) and 7 in the downstream sequence (DSS) of the 3′-flanking region, with 7 further mutations being treated as isolated examples. All the UCPAS mutations and the rather unusual cases of the DMPK, SCA8, FCMD and GLA mutations exert a significant effect on the mRNA phenotype and are usually associated with monogenic disease. By contrast, most of the remaining variants are polymorphisms that exert a comparatively minor influence on mRNA expression, but which may nevertheless predispose to or otherwise modify complex clinical phenotypes. Considerable efforts have been made to validate/elucidate the mechanisms through which the 3′ untranslated region (3’ UTR) variants affect gene expression. It is hoped that the integrative approach employed here in the study of naturally occurring variants of actual or potential pathological significance will serve to complement ongoing efforts to identify all functional regulatory elements in the human genome.


Cleavage Site Alternative Polyadenylation Translational Termination Codon IL2RG Gene Cleavage Site Recognition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



JMC is a visiting Professor of Genetics supported by the Ministère de la Jeunesse, de l’Éducation Nationale et de la Recherche, France. This work was supported by the INSERM (Institut National de la Santé et de la Recherche Médicale), France. The authors are most grateful to Peter Stenson for provision of HGMD data.

Supplementary material

439_2006_180_MOESM1_ESM.doc (58 kb)
Supplementary material


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Jian-Min Chen
    • 1
    • 2
    • 3
    Email author
  • Claude Férec
    • 1
    • 2
    • 3
    • 5
  • David N. Cooper
    • 4
  1. 1.INSERM, U613BrestFrance
  2. 2.Etablissement Français du Sang—BretagneBrestFrance
  3. 3.Faculté de Médecine de Brest et des Sciences de la SantéUniversité de Bretagne OccidentaleBrestFrance
  4. 4.Institute of Medical GeneticsCardiff UniversityCardiffUK
  5. 5.Laboratoire de Génétique Moléculaire et d’HistocompatibilitéCHRU Brest, Hôpital MorvanBrestFrance

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