LEMD3 – Buschke-Ollendorff syndrome

Buschke-Ollendorff syndrome (BOS) is a rare autosomal dominant connective tissue disorder characterized by asymptomatic connective tissue nevi and sclerotic bone lesions known as osteopoikilosis. Clinical diagnosis is based on radiographic identification of discrete osteosclerotic islands and histopathology of elastic fibre–rich nevi. Early linkage and mutational analyses mapped BOS to chromosome 12q14 and identified heterozygous loss-of-function variants in LEMD3 as causal in three multiplex families and one sporadic case (PMID:15489854).

Genetic evidence comprises >27 distinct nonsense, frameshift, and splice-site mutations reported in over 164 affected individuals across multiple unrelated pedigrees, with segregation demonstrated in three families (PMID:15489854; PMID:19438932). A recurrent heterozygous nonsense mutation, c.2203C>T (p.Arg735Ter), exemplifies the spectrum of truncating alleles disrupting the C-terminal Smad-binding domain. Phenotypic expressivity is highly variable, ranging from isolated osteopoikilosis to full BOS, without a clear genotype–phenotype correlation in isolated melorheostosis cases.

Functional studies demonstrate that the nucleoplasmic C-terminal domain of MAN1 (LEMD3) binds R-Smad2 and Smad3, antagonizing transforming growth factor-β signaling and modulating BMP/TGF-β pathways in human cells (PMID:15601644). Concordant in vivo models in Xenopus and cell-based assays confirm that MAN1 is essential for proper nuclear envelope–smad interactions and downstream transcriptional repression, supporting haploinsufficiency as the pathogenic mechanism.

No studies to date have refuted the BOS association, though absent LEMD3 mutations in rare families suggest possible genetic heterogeneity. Overall, the weight of genetic segregation and functional concordance supports a Strong gene–disease association. Clinically, heterozygous LEMD3 sequencing is recommended for definitive diagnosis, genetic counseling, and management of BOS patients.

Key Take-home: LEMD3 haploinsufficiency causes autosomal dominant Buschke-Ollendorff syndrome with variable penetrance; genetic testing enables accurate diagnosis and informs family counseling.

References

• Nature genetics • 2004 • Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. PMID:15489854
• Human molecular genetics • 2005 • MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. PMID:15601644
• Clinical genetics • 2009 • Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis. PMID:19438932

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