Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells.
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Jan
J
Hellemans
Olena
O
Preobrazhenska
Andy
A
Willaert
Philippe
P
Debeer
Peter C M
PC
Verdonk
Teresa
T
Costa
Katrien
K
Janssens
Bjorn
B
Menten
Nadine
N
Van Roy
Stefan J T
SJ
Vermeulen
Ravi
R
Savarirayan
Wim
W
Van Hul
Filip
F
Vanhoenacker
Danny
D
Huylebroeck
Anne
A
De Paepe
Jean-Marie
JM
Naeyaert
Jo
J
Vandesompele
Frank
F
Speleman
Kristin
K
Verschueren
Paul J
PJ
Coucke
Geert R
GR
Mortier
D001483:Base Sequence; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D004268:DNA-Binding Proteins; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008557:Melorheostosis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009506:Nevus / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010023:Osteopoikilosis / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome
D004268:DNA-Binding Proteins; C405329:LEMD3 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins