LEMD3 – Osteopoikilosis

LEMD3 encodes the inner nuclear membrane protein MAN1, which antagonizes bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) signaling to regulate skeletal homeostasis. Heterozygous loss-of-function variants in LEMD3 cause osteopoikilosis, an autosomal dominant condition characterized by symmetric, radiographically detectable hyperostotic bone islands often discovered incidentally (PMID:15489854). Osteopoikilosis may be isolated or part of Buschke-Ollendorff syndrome but remains benign with preserved bone architecture and no increased fracture risk.

In a three-generation Chinese family with six affected individuals, a novel heterozygous frameshift variant, c.2612_2613insA (p.Tyr871Ter), co-segregated fully with osteopoikilosis and was absent in 100 ethnically matched controls (PMID:26694706).

A landmark linkage and mutation analysis in three unrelated families identified over 20 probands harboring heterozygous LEMD3 loss-of-function variants—including frameshifts (e.g., c.1321_1324del [p.Tyr441fs]) and canonical splice-site mutations—establishing allelism between osteopoikilosis, Buschke-Ollendorff syndrome, and, less consistently, melorheostosis (PMID:15489854). Additional case reports have confirmed recurrent nonsense variants such as c.2203C>T (p.Arg735Ter) in families with variable expressivity.

Segregation analysis across multiple pedigrees demonstrates co-segregation of LEMD3 variants with disease in at least six additional affected relatives beyond index cases, consistent with autosomal dominant inheritance and high penetrance in bone phenotypes.

Functional studies reveal that the C-terminal domain of MAN1 binds Smad2 and Smad3 to antagonize TGF-β signaling, and overexpression of MAN1 attenuates TGF-β-induced transcription and growth arrest in cell models (PMID:15601644). In Xenopus laevis, RNAi-mediated depletion of the MAN1 ortholog causes lethal mitotic defects and underscores LEM domain protein importance in embryogenesis (PMID:12684533).

Collectively, the extensive case-level evidence, familial segregation, and concordant functional data support a definitive role for heterozygous LEMD3 haploinsufficiency in autosomal dominant osteopoikilosis. Genetic testing for LEMD3 loss-of-function variants enables precise diagnosis, informs family counseling, and guides management. Key take-home: LEMD3 loss-of-function variants are a definitive cause of autosomal dominant osteopoikilosis via disrupted BMP/TGF-β signaling.

References

• Nature Genetics • 2004 • Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. PMID:15489854
• Journal of Endocrinological Investigation • 2016 • Identification of a novel LEMD3 Y871X mutation in a three-generation family with osteopoikilosis and review of the literature. PMID:26694706
• 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
• Proceedings of the National Academy of Sciences • 2003 • MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans. PMID:12684533

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