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LEMD3 gene

Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

LEMD3 gene

The LEMD3 gene encodes a protein that regulates bone growth signaling pathways, and mutations in this gene are linked to connective tissue and bone density disorders.

Normal Function

The LEMD3 gene provides instructions for making a protein that is located in a cell structure called the nuclear envelope. The nuclear envelope surrounds the nucleus, acting as a barrier between the nucleus and the rest of the cell.

The LEMD3 protein helps control two chemical signaling pathways called the transforming growth factor beta (TGF-β) pathway and the bone morphogenic protein (BMP) pathway. The TGF-β and BMP pathways regulate various cellular processes, including cell growth and division (proliferation), the process by which cells mature to carry out special functions (differentiation), and the self-destruction of cells (apoptosis). These pathways are also involved in the growth of new bone.

Signaling through the BMP and TGF-β pathways turns on (activates) proteins called Smads, which attach (bind) to specific areas of DNA to activate certain genes. The LEMD3 protein interacts with Smads to reduce signaling through these pathways. In this way, the LEMD3 protein helps keep signaling at normal levels within the cell.

Health Conditions Related to Genetic Changes

Buschke-Ollendorff syndrome

At least 23 mutations in the LEMD3 gene have been found to cause Buschke-Ollendorff syndrome, a rare connective tissue disorder. The condition is characterized by skin growths called connective tissue nevi and bone abnormalities, most commonly osteopoikilosis. Osteopoikilosis refers to small, round areas of increased bone density that can be seen on x-rays. Rarely, people with Buschke-Ollendorff syndrome have another bone abnormality called melorheostosis, which is characterized by excess bone growth on the surface of existing bones in a pattern resembling dripping candle wax.

Each of the known LEMD3 gene mutations prevents the production of functional LEMD3 protein from one copy of the gene in each cell, which reduces the total amount of LEMD3 protein by about half. A shortage of this protein increases signaling through the BMP and TGF-β pathways. Studies suggest that the enhanced signaling increases the formation of bone tissue, resulting in areas of overly dense bone or excess bone growth.

Other disorders

LEMD3 gene mutations have also been found in people with isolated osteopoikilosis, a condition involving areas of increased bone density without the other features of Buschke-Ollendorff syndrome. Occasionally, mutations in this gene cause osteopoikilosis and melorheostosis without connective tissue nevi.

Other Names for This Gene

  • inner nuclear membrane protein Man1
  • integral inner nuclear membrane protein
  • LEM domain-containing protein 3
  • MAN1
  • MAN1_HUMAN

Frequently Asked Questions

Buschke-Ollendorff syndrome is characterized by the combination of skin lesions and distinctive bone abnormalities. The skin manifestations include connective tissue nevi (elastomas or collagenomas), which present as subtle, flesh-colored or yellowish plaques and papules. The skeletal manifestation is most commonly osteopoikilosis, marked by widespread, asymptomatic, round or ovoid densities within the bones that appear as spotted bone disease on X-rays.
Osteopoikilosis produces symmetric, small, well-demarcated sclerotic foci concentrated in the ends of long bones and the pelvic girdle, without cortical disruption or soft tissue masses. Crucially, a radionuclide bone scan (scintigraphy) usually shows normal or only minimally increased tracer uptake in osteopoikilosis, whereas osteoblastic metastases (such as from prostate or breast cancer) produce intensely hot, irregular, and asymmetric lesions that provoke bone remodeling and pain.
Osteopoikilosis itself is almost always completely painless and does not increase the risk of pathological bone fractures. However, a small subset of patients develop melorheostosis, an asymmetric hyperostosis resembling dripping candle wax on bone surfaces. Melorheostosis can cause significant localized pain, joint contractures, limb stiffness, leg-length discrepancies, and muscle atrophy that may require orthopedic and physical therapy intervention.
The condition is inherited in an autosomal dominant pattern, giving an affected parent a 50 percent chance of passing the altered LEMD3 gene to each child. Clinical expression varies substantially even within the same family; a parent with only a few unnoticeable skin papules may have a child who exhibits extensive osteopoikilosis or joint stiffness. Skeletal X-rays and skin examinations are recommended for first-degree relatives when a familial mutation is identified.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.