Copyright © 2004 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 74, Issue 2, 298-305, 1 February 2004
doi:10.1086/381715
Null Leukemia Inhibitory Factor Receptor (LIFR) Mutations in Stüve-Wiedemann/Schwartz-Jampel Type 2 Syndrome
Nathalie Dagoneau1, Deborah Scheffer1, Céline Huber1, Lihadh I. Al-Gazali3, Maja Di Rocco4, Anne Godard5, Jelena Martinovic1, Annick Raas-Rothschild6, Sabine Sigaudy7, Sheila Unger8, Sophie Nicole2, Bertrand Fontaine2, Jean-Luc Taupin9, Jean-François Moreau9, Andrea Superti-Furga10, Martine Le Merrer1, Jacky Bonaventure1, Arnold Munnich1, Laurence Legeai-Mallet1 and Valérie Cormier-Daire1, 
, 
1 Department of Medical Genetics and INSERM U393, Hôpital Necker-Enfants Malades, Faculté de Médecine Pitié-Salpêtrière, Paris
2 INSERM U546, Faculté de Médecine Pitié-Salpêtrière, Paris
3 Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain
4 Second Unit of Pediatrics, Istituto G. Gaslini, Genoa
5 INSERM U463, Institut de Biologie, Nantes, France
6 Department of Genetics, Hadassah University Medical Center, Jerusalem
7 Hôpital d’Enfants de La Timone, Marseille
8 Division of Clinical and Genetic Metabolics, University of Toronto, Toronto
9 CNRS UMR 5540, Université Bordeaux 2, Bordeaux
10 Department of Pediatrics, University of Lausanne, Lausanne
Address for correspondence and reprints: Dr. Valérie Cormier-Daire, Department of Medical Genetics, Hôpital Necker-Enfants Malades, 149 rue de Sevres, 75015 Paris, FranceAbstract
Stüve-Wiedemann syndrome (SWS) is a severe autosomal recessive condition characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality. Clinical overlap with Schwartz-Jampel type 2 syndrome (SJS2) has suggested that SWS and SJS2 could be allelic disorders. Through studying a series of 19 families with SWS/SJS2, we have mapped the disease gene to chromosome 5p13.1 at locus D5S418 (Zmax=10.66 at θ=0) and have identified null mutations in the leukemia inhibitory factor receptor (LIFR or gp190 chain) gene. A total of 14 distinct mutations were identified in the 19 families. An identical frameshift insertion (653_654insT) was identified in families from the United Arab Emirates, suggesting a founder effect in that region. It is interesting that 12/14 mutations predicted premature termination of translation. Functional studies indicated that these mutations alter the stability of LIFR messenger RNA transcripts, resulting in the absence of the LIFR protein and in the impairment of the JAK/STAT3 signaling pathway in patient cells. We conclude, therefore, that SWS and SJS2 represent a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene on chromosome 5p13.
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