Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis

Mutations in the LEMD3 gene were recently incriminated in Buschke–Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two‐generation BOS family showing an extremel...

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Bibliographic Details
Published in:	Clinical genetics 2009-06, Vol.75 (6), p.556-561
Main Authors:	Zhang, Y, Castori, M, Ferranti, G, Paradisi, M, Wordsworth, BP
Format:	Article
Language:	eng
Subjects:	Adult Base Sequence Biological and medical sciences Bone and Bones - pathology Bone diseases Buschke-Ollendorff syndrome Child Connective Tissue Diseases - genetics Connective Tissue Diseases - pathology Diseases of the osteoarticular system DNA-Binding Proteins Female Fundamental and applied biological sciences. Psychology General aspects. Genetic counseling Genetic disorders Genetics of eukaryotes. Biological and molecular evolution Genotype & phenotype Germ-Line Mutation Humans LEMD3 Male Malformations and congenital and or hereditary diseases involving bones. Joint deformations Medical genetics Medical sciences melorheostosis Melorheostosis - genetics Melorheostosis - pathology Membrane Proteins - genetics Molecular and cellular biology Molecular Sequence Data Mutation Nuclear Proteins - genetics osteopoikilosis Osteopoikilosis - genetics Osteopoikilosis - pathology Sequence Analysis, DNA Skin - pathology Syndrome variable expression
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Summary:	Mutations in the LEMD3 gene were recently incriminated in Buschke–Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two‐generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype–genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation.
ISSN:	0009-9163 1399-0004