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Genetics Home Reference: your guide to understanding genetic conditions
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LEMD3

Reviewed October 2013

What is the official name of the LEMD3 gene?

The official name of this gene is “LEM domain containing 3.”

LEMD3 is the gene's official symbol. The LEMD3 gene is also known by other names, listed below.

What is the normal function of the LEMD3 gene?

The LEMD3 gene provides instructions for making a protein that is located in the inner membrane of the nuclear envelope. The nuclear envelope is a cell structure that 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. Signaling through these pathways turns on (activates) proteins called Smads, which attach (bind) to specific areas of DNA to activate certain genes. 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.

The LEMD3 protein interacts with Smads to reduce signaling through the BMP and TGF-β pathways. In this way, the LEMD3 protein helps keep signaling at normal levels within the cell.

How are changes in the LEMD3 gene related to health conditions?

Buschke-Ollendorff syndrome - caused by mutations in the LEMD3 gene

At least 23 mutations in the LEMD3 gene have been found to cause Buschke-Ollendorff syndrome, a rare connective tissue disorder. (Connective tissues provide strength and flexibility to structures throughout the body.) The condition is characterized by connective tissue nevi and osteopoikilosis. Connective tissue nevi are small, noncancerous lumps on the skin that are widespread in people with this disorder. Osteopoikilosis is a skeletal abnormality characterized by small, round areas of increased bone density that can be seen on x-rays.

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 prevents it from controlling BMP and TGF-β signaling effectively, leading to increased signaling through both of these pathways. Studies suggest that the enhanced signaling increases the formation of bone tissue, resulting in areas of overly dense bone. It is unclear how the abnormal signaling is related to the development of connective tissue nevi in people with Buschke-Ollendorff syndrome.

other disorders - caused by mutations in the LEMD3 gene

LEMD3 gene mutations have also been found in people with isolated osteopoikilosis, a condition involving areas of increased bone density that occur without the connective tissue nevi that characterize Buschke-Ollendorff syndrome. Occasionally, osteopoikilosis occurs with another, more severe skeletal abnormality called melorheostosis. This abnormality causes the outer layers of bones to become overly thick and dense, and it tends to be limited to one arm or leg. Melorheostosis can be associated with pain, stiffness, and restricted joint movement that worsen over time.

Researchers are working to determine how LEMD3 gene mutations cause Buschke-Ollendorff syndrome in some people and isolated osteopoikilosis or osteopoikilosis with melorheostosis in others. In some cases, the same mutation has been found to cause all of these conditions in different members of a single family. Each of the known mutations reduces the amount of functional LEMD3 protein that is produced in cells, which abnormally enhances BMP and TGF-β signaling and leads to areas of increased bone density.

Where is the LEMD3 gene located?

Cytogenetic Location: 12q14

Molecular Location on chromosome 12: base pairs 65,169,570 to 65,248,360

The LEMD3 gene is located on the long (q) arm of chromosome 12 at position 14.

The LEMD3 gene is located on the long (q) arm of chromosome 12 at position 14.

More precisely, the LEMD3 gene is located from base pair 65,169,570 to base pair 65,248,360 on chromosome 12.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about LEMD3?

You and your healthcare professional may find the following resources about LEMD3 helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the LEMD3 gene or gene products?

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

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding LEMD3?

apoptosis ; bone density ; cell ; connective tissue ; differentiation ; DNA ; domain ; gene ; growth factor ; joint ; mutation ; nuclear envelope ; nuclear membrane ; nucleus ; proliferation ; protein ; syndrome ; tissue ; x-rays

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Burger B, Hershkovitz D, Indelman M, Kovac M, Galambos J, Haeusermann P, Sprecher E, Itin PH. Buschke-Ollendorff syndrome in a three-generation family: influence of a novel LEMD3 mutation to tropoelastin expression. Eur J Dermatol. 2010 Nov-Dec;20(6):693-7. doi: 10.1684/ejd.2010.1051. Epub 2010 Aug 24. (http://www.ncbi.nlm.nih.gov/pubmed/20732851?dopt=Abstract)
  • Couto AR, Bruges-Armas J, Peach CA, Chapman K, Brown MA, Wordsworth BP, Zhang Y. A novel LEMD3 mutation common to patients with osteopoikilosis with and without melorheostosis. Calcif Tissue Int. 2007 Aug;81(2):81-4. Epub 2007 Jul 11. (http://www.ncbi.nlm.nih.gov/pubmed/17622481?dopt=Abstract)
  • Hellemans J, Preobrazhenska O, Willaert A, Debeer P, Verdonk PC, Costa T, Janssens K, Menten B, Van Roy N, Vermeulen SJ, Savarirayan R, Van Hul W, Vanhoenacker F, Huylebroeck D, De Paepe A, Naeyaert JM, Vandesompele J, Speleman F, Verschueren K, Coucke PJ, Mortier GR. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004 Nov;36(11):1213-8. Epub 2004 Oct 17. (http://www.ncbi.nlm.nih.gov/pubmed/15489854?dopt=Abstract)
  • Lin F, Blake DL, Callebaut I, Skerjanc IS, Holmer L, McBurney MW, Paulin-Levasseur M, Worman HJ. MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. J Biol Chem. 2000 Feb 18;275(7):4840-7. (http://www.ncbi.nlm.nih.gov/pubmed/10671519?dopt=Abstract)
  • Lin F, Morrison JM, Wu W, Worman HJ. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum Mol Genet. 2005 Feb 1;14(3):437-45. Epub 2004 Dec 15. (http://www.ncbi.nlm.nih.gov/pubmed/15601644?dopt=Abstract)
  • Mumm S, Wenkert D, Zhang X, McAlister WH, Mier RJ, Whyte MP. Deactivating germline mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff syndrome, but not sporadic melorheostosis. J Bone Miner Res. 2007 Feb;22(2):243-50. (http://www.ncbi.nlm.nih.gov/pubmed/17087626?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/23592)
  • Zhang Y, Castori M, Ferranti G, Paradisi M, Wordsworth BP. Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis. Clin Genet. 2009 Jun;75(6):556-61. doi: 10.1111/j.1399-0004.2009.01177.x. Epub 2009 May 5. Erratum in: Clin Genet. 2011 Apr;79(4):401. (http://www.ncbi.nlm.nih.gov/pubmed/19438932?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: October 2013
Published: April 21, 2014