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.
Hellemans
Jan
J
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Preobrazhenska
Olena
O
Willaert
Andy
A
Debeer
Philippe
P
Verdonk
Peter C M
PC
Costa
Teresa
T
Janssens
Katrien
K
Menten
Bjorn
B
Van Roy
Nadine
N
Vermeulen
Stefan J T
SJ
Savarirayan
Ravi
R
Van Hul
Wim
W
Vanhoenacker
Filip
F
Huylebroeck
Danny
D
De Paepe
Anne
A
Naeyaert
Jean-Marie
JM
Vandesompele
Jo
J
Speleman
Frank
F
Verschueren
Kristin
K
Coucke
Paul J
PJ
Mortier
Geert R
GR
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