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ALX4 gene

ALX homeobox 4
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Normal Function

The ALX4 gene provides instructions for making a member of the homeobox protein family. Homeobox proteins direct the formation of body structures during early embryonic development. The ALX4 protein is necessary for normal development of the skull and formation of the head and face, which begins early in fetal development. This protein is also involved in the formation of skin layers, but its role in this process is poorly understood.

The ALX4 protein is a transcription factor, which means that it attaches (binds) to DNA and controls the activity of certain genes. Specifically, the protein controls the activity of genes that regulate cell growth and division (proliferation), cell maturation and specialization (differentiation), cell movement (migration), and cell survival. The regulation of these functions ensures that cells start and stop growing at specific times and that they are positioned correctly during development.

Health Conditions Related to Genetic Changes

Enlarged parietal foramina

At least eight mutations in the ALX4 gene have been found to cause enlarged parietal foramina type 2. This condition is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. Openings in the parietal bones are normal during fetal development, but they usually close before birth. In people with this condition, the parietal foramina remain open throughout life.

The mutations that cause enlarged parietal foramina result in the production of an ALX4 protein that cannot bind to DNA, which alters the regulation of multiple genes. As a result, several cell processes are disrupted, including proliferation, differentiation, and survival. In early development, the skull seems to be particularly sensitive to changes in ALX4 protein activity. Specifically, cells in the skull that are involved in bone formation (ossification) cannot function normally, leading to a lack of bone in areas of the skull and resulting in enlarged parietal foramina.

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Frontonasal dysplasia

At least four mutations in the ALX4 gene have been found to cause frontonasal dysplasia. ALX4 gene mutations cause a form of the disorder called frontonasal dysplasia type 2. In addition to facial malformations, this type can include features such as genital abnormalities in males, hair loss (alopecia), and enlarged parietal foramina (described above). The ALX4 gene mutations that cause frontonasal dysplasia type 2 severely reduce or eliminate the function of the ALX4 protein. As a result, the protein cannot bind to DNA and regulate gene function, which leads to poorly controlled cell proliferation and migration during development. This abnormal cell growth and movement leads to malformations in the middle of the face, particularly affecting the nose, which leads to openings (clefts) in the nose. This abnormal development can also interfere with the proper formation of the skull, which likely contributes to enlarged parietal foramina. In some individuals, ALX4 gene mutations impair the function of hair follicles and lead to alopecia, but the mechanism is unclear.

Because enlarged parietal foramina can be a feature of frontonasal dysplasia type 2 and because the two conditions are caused by mutations in the same gene, it is unclear whether these conditions are distinct disorders or part of a disease spectrum.

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Potocki-Shaffer syndrome

A mutation resulting in the deletion of the ALX4 gene causes a condition called Potocki-Shaffer syndrome. People with this condition have enlarged parietal foramina (described above) and multiple noncancerous bone tumors (osteochondromas). Other signs and symptoms seen in some people with Potocki-Shaffer syndrome include intellectual disability, developmental delay, distinctive facial features, vision problems, and defects in the heart, kidneys, and urinary tract.

Potocki-Shaffer syndrome (also called proximal 11p deletion syndrome) is caused by a deletion of genetic material from the short (p) arm of chromosome 11. In people with this condition, a loss of the ALX4 gene within this region is responsible for enlarged parietal foramina. This feature occurs because a shortage of the ALX4 transcription factor caused by deletion of the gene disrupts several cellular processes and impairs proper bone formation (ossification). The loss of additional genes in the deleted region likely contributes to the other features of Potocki-Shaffer syndrome. Specifically, loss of the EXT2 gene results in multiple osteochondromas, and deletion of the PHF21A gene causes intellectual disability and distinctive facial features.

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Other Names for This Gene

  • ALX4_HUMAN
  • FPP
  • homeodomain transcription factor ALX4
  • KIAA1788
  • PFM
  • PFM2

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Griessenauer CJ, Veith P, Mortazavi MM, Stewart C, Grochowsky A, Loukas M, Tubbs RS. Enlarged parietal foramina: a review of genetics, prognosis, radiology, and treatment. Childs Nerv Syst. 2013 Apr;29(4):543-7. doi: 10.1007/s00381-012-1982-7. Epub 2012 Dec 4. Review. Citation on PubMed
  • Hall CR, Wu Y, Shaffer LG, Hecht JT. Familial case of Potocki-Shaffer syndrome associated with microdeletion of EXT2 and ALX4. Clin Genet. 2001 Nov;60(5):356-9. Citation on PubMed
  • Kariminejad A, Bozorgmehr B, Alizadeh H, Ghaderi-Sohi S, Toksoy G, Uyguner ZO, Kayserili H. Skull defects, alopecia, hypertelorism, and notched alae nasi caused by homozygous ALX4 gene mutation. Am J Med Genet A. 2014 May;164A(5):1322-7. doi: 10.1002/ajmg.a.36008. Epub 2014 Mar 25. Citation on PubMed
  • Kayserili H, Altunoglu U, Ozgur H, Basaran S, Uyguner ZO. Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations. Am J Med Genet A. 2012 Jan;158A(1):236-44. doi: 10.1002/ajmg.a.34390. Epub 2011 Dec 2. Citation on PubMed
  • Kayserili H, Uz E, Niessen C, Vargel I, Alanay Y, Tuncbilek G, Yigit G, Uyguner O, Candan S, Okur H, Kaygin S, Balci S, Mavili E, Alikasifoglu M, Haase I, Wollnik B, Akarsu NA. ALX4 dysfunction disrupts craniofacial and epidermal development. Hum Mol Genet. 2009 Nov 15;18(22):4357-66. doi: 10.1093/hmg/ddp391. Epub 2009 Aug 19. Citation on PubMed
  • Mavrogiannis LA, Wilkie AOM. Enlarged Parietal Foramina. 2004 Mar 30 [updated 2019 Nov 27]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews┬« [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1128/ Citation on PubMed
  • Romeike BF, Wuyts W. Proximal chromosome 11p contiguous gene deletion syndrome phenotype: case report and review of the literature. Clin Neuropathol. 2007 Jan-Feb;26(1):1-11. Review. Citation on PubMed
  • Wakui K, Gregato G, Ballif BC, Glotzbach CD, Bailey KA, Kuo PL, Sue WC, Sheffield LJ, Irons M, Gomez EG, Hecht JT, Potocki L, Shaffer LG. Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki-Shaffer syndrome. Eur J Hum Genet. 2005 May;13(5):528-40. Citation on PubMed
  • Wu YQ, Badano JL, McCaskill C, Vogel H, Potocki L, Shaffer LG. Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Am J Hum Genet. 2000 Nov;67(5):1327-32. Epub 2000 Oct 3. Citation on PubMed or Free article on PubMed Central
  • Wuyts W, Cleiren E, Homfray T, Rasore-Quartino A, Vanhoenacker F, Van Hul W. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J Med Genet. 2000 Dec;37(12):916-20. Citation on PubMed or Free article on PubMed Central
  • Wuyts W, Waeber G, Meinecke P, Sch├╝ler H, Goecke TO, Van Hul W, Bartsch O. Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects. Eur J Hum Genet. 2004 May;12(5):400-6. Review. Citation on PubMed
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