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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.

Original publication




Journal article


Calcified tissue international

Publication Date





81 - 84


Serviço Especializado de Epidemiologia e Biologia Molecular, Hospital de Santo Espírito and Instituto de Biologia Molecular e Celular da Universidade do Porto, Angra do Heroísmo, Açores, GARG/IBMC, 9700-856, Porto, Portugal.


Bone and Bones, Humans, Melorheostosis, Osteopoikilosis, Genetic Predisposition to Disease, Membrane Proteins, Nuclear Proteins, DNA, Codon, Nonsense, Genetic Markers, Pedigree, DNA Mutational Analysis, Base Sequence, Genotype, Heterozygote, Mutation, Exons, Adult, Azores, Ireland, Female, Male, Genetic Testing