Identification of a new group of genetic mutations

April 08 2011

For the first time, Patrick Edery from the Centre de recherche en neurosciences de Lyon (Inserm/CNRS/Université de Lyon 1) and Anne-Louise Leutenegger from Inserm Unit 946 "Variabilité génétique et maladies humaines" in Paris together with their collaborators have described a new group of genetic mutations using genome sequencing. The scientists have demonstrated the involvement of a small RNA molecule in a human genetic disease (Taybi-Linder syndrome). This small RNA, called snRNA - small nuclear RNA - is involved in a crucial step which precedes protein synthesis. In the long term, the discovery of mutations in the snRNA should allow rapid identification of the genes involved in development of the brain, bones and other tissues. This could lead to therapeutic possibilities. These results were published in the journal Science on 8 April 2011.

The maturation of the precursor mRNA, a critical precursor step for protein synthesis

The maturation of the precursor mRNA, a critical precursor step for protein synthesis

During embryonic development, genetic information carried in the deoxyribonucleic acid (DNA), organized in genes, undergoes several operations which result in the synthesis of the proteins that go to the make up the organism.

During embryonic development, genetic information carried in the deoxyribonucleic acid (DNA), organized in genes, undergoes several operations which result in the synthesis of the proteins that go to the make up the organism.

This information is first transcribed into messenger ribonucleic acid (RNA) and then translated into proteins. In the eukaryotes there is an intermediate stage of precursor mRNA maturation. This process known as "RNA splicing", occurs through the action of the "spliceosome", a special tool made up of small snRNA (1) molecules and proteins. This complex is able to remove non-coding parts of the precursor mRNA, known as "introns", and to weld together the coding cells, known as "exons", which will later be used during protein synthesis (see figure opposite).

In this work, the researchers uncovered an anomaly within the spliceosome which is an essential participant in the processes before protein synthesis, from the time of embryonic development and throughout pre-and postnatal life.

The scientists have identified an anomaly in the small snRNA molecules of the spliceosome among patients exhibiting rapid postnatal death and serious deformities of the brain, bones and other tissues (microcephalic primordial dwarfism type 1. MOPD1, or Taybi Linder syndrome, TALS). "For the first time, the use of a new statistical method (2) has made it possible to locate the genetic fault on a small region of chromosome 2. Then, recent rapid sequencing techniques allowed the identification of 4 mutations linked to the snRNA known as U4atac", emphasizes Anne Louise Leutenegger. According to the researchers, these mutations are responsible for early death, several months after birth, and severe deformities of the brain and bones observed in patients afflicted with Taybi Linder syndrome (3).

"Thanks to this discovery, it is now possible to propose an early prenatal diagnosis of this very serious affliction and, beyond this, identification of the proteins affected by this anomaly may make it possible to consider therapeutic strategies which would make death avoidable", explains Patrick Edery.

More important still, this is a question of the first involvement of a small snRNA molecule from the "spliceosome" complex in a genetic disease. This work indicates that effective splicing, i.e. maturation of the precursor mRNA, is required for normal embryonic development and for postnatal life in man. Indeed, an anomaly observed upstream of protein synthesis has important repercussions on all stages of the embryonic and postnatal development of individuals.

"The discovery of this new mechanism responsible for development anomalies should make it possible, using the genome sequencing technique, to identify many genes involved in serious genetic deformities", concludes Patrick Edery.


(1) snRNA: small nuclear ribonucleic acid, contained in the nucleus of the cell
(2) Using genomic inbreeding coefficient estimates for homozygosity mapping of rare recessive traits: application to Taybi-Linder syndrome. Leutenegger AL, Labalme A, Genin E, Toutain A, Steichen E, Clerget-Darpoux F, Edery P. Am J Hum Genet. 2006; 79(1):62-6
(3) MOPD1 or Taybi-Linder syndrome: a serious genetic disease which can induce death just after birth or serious deformities of the brain, bones and other tissues. Currently, the prevalence of the disease is unknown and around 30 cases have been described in literature.

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"Association of TALS Developmental Disorder with Defect in Minor Splicing Component - U4atac snRNA"

Patrick EDERY 1,2†, Charles MARCAILLOU 3*, Mourad SAHBATOU 4*, Audrey LABALME 1*, Joelle CHASTANG 1, Renaud TOURAINE 5, Emmanuel TUBACHER 4, Faiza SENNI 1, Michael B. BOBER 6, Sheela NAMPOOTHIRI 7, Pierre-Simon JOUK 8,9, Elisabeth STEICHEN 10, Siren BERLAND 11,12, Annick TOUTAIN 13,14, Carol A. WISE 15, Damien SANLAVILLE 1,2, Francis ROUSSEAU 3, Françoise CLERGET-DARPOUX 16,17, Anne-Louise LEUTENEGGER18,19

* These authors contributed equally to this work
(1) Hospices Civils de Lyon, Service de Cytogénétique Constitutionnelle, Bron, F-69677, France
(2) Inserm U1028, CNRS UMR5292, Université Lyon 1, CRNL, TIGER, Lyon, F-69000, France
(3) IntegraGen SA, Evry, F-91030, France
(4) Fondation Jean Dausset - Centre d’Etude du Polymorphisme Humain, Paris, F-75010, France
(5) CHU-Hôpital Nord, Service de Génétique, Saint-Etienne, F-42055, France
(6) Department of Pediatrics, Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, DE 19803, USA
(7) Amrita Institute of Medical Sciences & Research Center, Department of Pediatric Genetics, Cochin, I-682041, India
(8) CHU Grenoble, Département de Génétique et Procréation, F-38043 Grenoble cedex9, France
(9) UJF-Grenoble1, CNRS TIMC UMR 5525, Grenoble, F-38041, France
(10) University Hospital Innsbruck, Department of Pediatrics, Innsbruck, A-6020, Austria
(11) Section of Clinical Genetics, Department of Pathology, St. Olavs Hospital, Trondheim, N-7006, Norway
(12) Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
(13) Service de Génétique, CHRU, Hôpital Bretonneau, Tours, F-37044, France
(14) INSERM U930, Université François Rabelais, Tours, France
(15) Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn St., Dallas, TX 75219, USA
(16) Inserm, U669, Villejuif, F-94804, France
(17) Université Paris Sud, UMR-S669, Villejuif, F-94804, France
(18) Inserm, U946, Paris, F-75010, France
(19) Université Paris Diderot, Institut Universitaire d’Hématologie, UMR-S946, Paris, F-75010, France

Science, 8 April 2011

Research contacts

Patrick Edery (medical geneticist)
Joint research unit UMR 1028 (Inserm/CNRS/Université Lyon 1) "Centre de recherche en neurosciences de Lyon"
Tel.: 04 72 12 96 98

Anne-Louise Leutenegger (epidemiological geneticist)
Inserm Unit 946 "Variabilité génétique et maladies humaines"
Tel.: 01 53 72 50 29

Press contact

Juliette Hardy
Tel.: 01 44 23 60 98

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