Recent studies have reported loss of function mutations in the LEMD3 gene, encoding an inner nuclear membrane
protein that influences Smad signaling, as a cause of
osteopoikilosis,
Buschke-Ollendorff syndrome, and
melorheostosis. We investigated LEMD3 in a three-generation family with
osteopoikilosis from the Azores, an affected father and daughter from Ireland with
osteopoikilosis (the daughter also had
melorheostosis), and two other individuals from the UK with isolated
melorheostosis. We found a novel C to T substitution at position 2032 bp (
cDNA) in exon 8 of LEMD3, resulting in a
premature stop codon at
amino acid position 678. This mutation co-segregates with the
osteopoikilosis phenotype in both the Azorean family and the Irish family. It was not detected in any of the six unaffected family members or in 342 healthy Caucasian individuals. No LEMD3 mutations were detected in the two patients with sporadic
melorheostosis. The LEMD3 mutation reported was clearly the cause of
osteopoikilosis in the two families but its relationship to
melorheostosis in one of the family members is still unclear. Perhaps unsurprisingly in what is a segmental disease, we did not find LEMD3 mutations in peripheral-blood-derived
DNA from the two other individuals with sporadic
melorheostosis. The nature of the additional genetic and/or environmental influences required for the development of
melorheostosis in those with
osteopoikilosis requires further investigation.