The SF3B4 gene provides instructions for making the SAP49 protein, which is part of a complex called a spliceosome. Spliceosomes help process messenger RNA (mRNA), which is a chemical cousin of DNA that serves as a genetic blueprint for making proteins. The spliceosomes recognize and then remove regions from mRNA molecules that are not used in the blueprint (which are called introns).
The SAP49 protein may also be involved in a chemical signaling pathway known as the bone morphogenic protein (BMP) pathway. This signaling pathway regulates various cellular processes and is involved in the growth of cells. The SAP49 protein is particularly important for the maturation of cells that build bones and cartilage (osteoblasts and chondrocytes).
Health Conditions Related to Genetic Changes
More than 30 mutations in the SF3B4 gene have been found to cause Nager syndrome, which is primarily characterized by abnormalities of the face, hands, and arms, such as underdeveloped cheek bones (malar hypoplasia), a small lower jaw (micrognathia), and malformed or absent thumbs. The condition can also affect development of other parts of the body. More than half of people with this condition have a mutation in the SF3B4 gene. These mutations prevent the production of SAP49 protein or lead to production of a nonfunctional protein. It is unclear how a shortage of functional SAP49 protein leads to the development problems in Nager syndrome. Researchers suspect that problems with spliceosome formation may impair mRNA processing and alter the activity of genes involved in development of several parts of the body. A loss of SAP49 may also impair BMP pathway signaling, leading to abnormal development of bones in the face, hands, and arms.More About This Health Condition
At least four SF3B4 gene mutations have been found to cause acrofacial dysostosis of Rodriguez, a severe disorder that causes underdevelopment of bones in the face, arms, and legs as well as lung abnormalities. Affected individuals have abnormally short arm bones, such that the hands are located very close to the body (phocomelia). In addition, the fingers, toes, and a bone in the lower leg called the fibula are usually missing. Affected individuals also have an opening in the roof of the mouth (cleft palate), small external ears (microtia), and micrognathia. In this condition, micrognathia is severe and leads to life-threatening breathing problems; most affected babies do not survive past birth.
The effects of the SF3B4 gene mutations that cause acrofacial dysostosis of Rodriguez are not understood. Similar to Nager syndrome (described above), researchers suspect that abnormal spliceosome function and disruption of the BMP signaling pathway impair normal bone development and limb formation in babies with this condition.
Other Names for This Gene
- pre-mRNA-splicing factor SF3b 49 kDa subunit
- SAP 49
- spliceosomal protein
- spliceosome-associated protein (U2 snRNP)
- spliceosome-associated protein 49
- splicing factor 3B subunit 4
- splicing factor 3b, subunit 4, 49kD
- splicing factor 3b, subunit 4, 49kDa
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, Siu V, Lauzon J, Fernandez BA, McMillin M, Scott RH, Racher H; FORGE Canada Consortium; Majewski J, Nickerson DA, Shendure J, Bamshad MJ, Parboosingh JS. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012 May 4;90(5):925-33. doi: 10.1016/j.ajhg.2012.04.004. Epub 2012 Apr 26. Citation on PubMed or Free article on PubMed Central
- Champion-Arnaud P, Reed R. The prespliceosome components SAP 49 and SAP 145 interact in a complex implicated in tethering U2 snRNP to the branch site. Genes Dev. 1994 Aug 15;8(16):1974-83. doi: 10.1101/gad.8.16.1974. Citation on PubMed
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- Irving MD, Dimitrov BI, Wessels M, Holder-Espinasse M, Chitayat D, Simpson MA. Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene. Am J Med Genet A. 2016 Dec;170(12):3133-3137. doi: 10.1002/ajmg.a.37946. Epub 2016 Sep 19. Citation on PubMed
- Marques F, Tenney J, Duran I, Martin J, Nevarez L, Pogue R, Krakow D, Cohn DH, Li B. Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis. PLoS Genet. 2016 Sep 13;12(9):e1006307. doi: 10.1371/journal.pgen.1006307. eCollection 2016 Sep. Erratum In: PLoS Genet. 2016 Dec 9;12 (12 ):e1006502. Citation on PubMed or Free article on PubMed Central
- Petit F, Escande F, Jourdain AS, Porchet N, Amiel J, Doray B, Delrue MA, Flori E, Kim CA, Marlin S, Robertson SP, Manouvrier-Hanu S, Holder-Espinasse M. Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clin Genet. 2014 Sep;86(3):246-51. doi: 10.1111/cge.12259. Epub 2013 Sep 12. Citation on PubMed
- Watanabe H, Shionyu M, Kimura T, Kimata K, Watanabe H. Splicing factor 3b subunit 4 binds BMPR-IA and inhibits osteochondral cell differentiation. J Biol Chem. 2007 Jul 13;282(28):20728-38. doi: 10.1074/jbc.M703292200. Epub 2007 May 18. Citation on PubMed