title: Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
abstract: Stuve-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 theta =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.
authors.affiliation: Department of Medical Genetics and INSERM U393, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dagoneau
authors.forename: Deborah
authors.initials: D
authors.lastname: Scheffer
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Lihadh I
authors.initials: LI
authors.lastname: Al-Gazali
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Anne
authors.initials: A
authors.lastname: Godard
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Annick
authors.initials: A
authors.lastname: Raas-Rothschild
authors.forename: Sabine
authors.initials: S
authors.lastname: Sigaudy
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Taupin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Jacky
authors.initials: J
authors.lastname: Bonaventure
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D001483:Base Sequence; D002648:Child; D002895:Chromosomes, Human, Pair 5; D017931:DNA Primers; D008040:Genetic Linkage; D006801:Humans; D007150:Immunohistochemistry; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D018121:Receptors, Cytokine / Q000235:genetics*; D053606:Receptors, OSM-LIF
chemical_list: D017931:DNA Primers; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF