Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome.
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.
Dagoneau
Nathalie
N
Department of Medical Genetics and INSERM U393, Hôpital Necker-Enfants Malades, Paris, France.
Scheffer
Deborah
D
Huber
Céline
C
Al-Gazali
Lihadh I
LI
Di Rocco
Maja
M
Godard
Anne
A
Martinovic
Jelena
J
Raas-Rothschild
Annick
A
Sigaudy
Sabine
S
Unger
Sheila
S
Nicole
Sophie
S
Fontaine
Bertrand
B
Taupin
Jean-Luc
JL
Moreau
Jean-François
JF
Superti-Furga
Andrea
A
Le Merrer
Martine
M
Bonaventure
Jacky
J
Munnich
Arnold
A
Legeai-Mallet
Laurence
L
Cormier-Daire
Valérie
V
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
D017931:DNA Primers; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF