LFNG
LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase, also known as LFNG and Lunatic Fringe,[1] is a human gene.[2]
This gene encodes a member of the glycosyltransferase superfamily. The encoded protein is a single-pass type II Golgi membrane protein that functions as a fucose-specific glycosyltransferase, adding an N-acetylglucosamine to the fucose residue of a group of signaling receptors involved in regulating cell fate decisions during development. Mutations in this gene have been associated with autosomal recessive spondylocostal dysostosis 3. Alternatively spliced transcript variants that encode different isoforms have been described, however, not all variants have been fully characterized.[2]
Function
Lunatic Fringe (Lfng) is a gene whose role in embryonic development is to establish the anterior boundary of somites, which will eventually develop in vertebrae, ribs, and dermis.[3] Lunatic Fringe responds to certain threshold ratios of retinoic acid and FGF-8 in order to mark the anterior boundary of somites while another transcription factor, Hairy, responds to different threshold ratios of retinoic acid and FGF-8 to form the posterior boundaries of somites.[4]
Clinical significance
A defect associated with Lfng mutations is spondylocostal dysostosis. Spondylocostal dysostosis is characterized by segmentation problems in the developing vertebrae resulting in fusion or lack of vertebrae along with abnormalities in the ribs.[5] Clinically, spondylocostal dysostosis presents as a shortened neck and trunk relative total height and a mild form of scoliosis. Respiratory problems are also common in spondylocostal dysostosis because of the shortened trunk.
A knockout model for Lfng has been created in mice, and without Lfng, mice have shorter tails, and impaired rib, lung, and somite development. A deficiency of Lfng in male mice has also been associated with lack of spermatozoa in the epididymis of many mice; however, spermatogenesis was not impaired. Rather, the male mice were subfertile.[6] In female mice, Lfng deficiency led to infertility because of abnormal folliculogenesis. Further examination showed that oocytes from these female mice did not complete meiotic maturation.[7] However, there are other studies that contradict this stating that not all female mile deficient of Lfng are infertile. A possible explanation for this difference between these studies is that the Lfng alleles were functional different, however, this is unlikely. More likely is that this discrepancy results from differences in the genetic background of the mice or husbandry and colony conditions.[8]
References
- ↑ Egan S, Herbrick JA, Tsui LC, Cohen B, Flock G, Beatty B, Scherer SW (1998). "Mapping of the human Lunatic Fringe (LFNG) gene to 7p22 and Manic Fringe (MFNG) to 22q12". Genomics 54 (3): 576–7. doi:10.1006/geno.1998.5559. PMID 9878264.
- 1 2 "Entrez Gene: LFNG LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase".
- ↑ Serth K, Schuster-Gossler K, Cordes R, Gossler A (April 2003). "Transcriptional oscillation of lunatic fringe is essential for somitogenesis". Genes Dev. 17 (7): 912–25. doi:10.1101/gad.250603. PMC 196028. PMID 12670869.
- ↑ Shifley ET, Vanhorn KM, Perez-Balaguer A, Franklin JD, Weinstein M, Cole SE (2008). "Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton". Development 135 (5): 899–908. doi:10.1242/dev.006742. PMID 18234727.
- ↑ Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL (2006). "Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype". Am. J. Hum. Genet. 78 (1): 28–37. doi:10.1086/498879. PMC 1380221. PMID 16385447.
- ↑ Hahn KL, Beres B, Rowton MJ, Skinner MK, Chang Y, Rawls A, Wilson-Rawls J (2009). "A deficiency of lunatic fringe is associated with cystic dilation of the rete testis". Reproduction 137 (1): 79–93. doi:10.1530/REP-08-0207. PMID 18801836.
- ↑ Hahn KL, Johnson J, Beres BJ, Howard S, Wilson-Rawls J (2005). "Lunatic fringe null female mice are infertile due to defects in meiotic maturation". Development 132 (4): 817–28. doi:10.1242/dev.01601. PMID 15659488.
- ↑ Xu J, Norton CR, Gridley T (2006). "Not all lunatic fringe null female mice are infertile". Development 133 (4): 579; author reply 579–80. doi:10.1242/dev.02221. PMID 16436621.
Further reading
- Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, Vogt TF (1997). "A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway". Development 124 (11): 2245–54. PMID 9187150.
- Moran JL, Johnston SH, Rauskolb C, Bhalerao J, Bowcock AM, Vogt TF (June 1999). "Genomic structure, mapping, and expression analysis of the mammalian Lunatic, Manic, and Radical fringe genes". Mamm. Genome 10 (6): 535–41. doi:10.1007/s003359901039. PMID 10341080.
- Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF (2000). "Fringe is a glycosyltransferase that modifies Notch". Nature 406 (6794): 369–75. doi:10.1038/35019000. PMID 10935626.
- Shimizu K, Chiba S, Saito T, Kumano K, Takahashi T, Hirai H (2001). "Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation". J. Biol. Chem. 276 (28): 25753–8. doi:10.1074/jbc.M103473200. PMID 11346656.
- Cole SE, Levorse JM, Tilghman SM, Vogt TF (2002). "Clock regulatory elements control cyclic expression of Lunatic fringe during somitogenesis". Dev. Cell 3 (1): 75–84. doi:10.1016/S1534-5807(02)00212-5. PMID 12110169.
- Shao L, Moloney DJ, Haltiwanger R (2003). "Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region". J. Biol. Chem. 278 (10): 7775–82. doi:10.1074/jbc.M212221200. PMID 12486116.
- Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS (2005). "Transcriptome analysis of human gastric cancer". Mamm. Genome 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674.
- Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL (2006). "Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype". Am. J. Hum. Genet. 78 (1): 28–37. doi:10.1086/498879. PMC 1380221. PMID 16385447.