Kinase Subfamily FAM20A

Kinase Classification: Group PKL: Family GASK: Subfamily FAM20A

FAM20A is a subfamily of the GASK (Golgi-Associated Kinase) family of secretory kinases. It consists of two genes (FAM20A and FAM20C) in humans and all other vertebrates, and one or more homologs in other deuterostomes, in insects and in nematodes.

Evolution

FAM20A is single copy in all vertebrates, but FAM20C is dynamic: it appears to be duplicated four-fold in most fish, though lost from some, and an additional likely paralog is found from amphibians to platypus, but not in placental mammals or fish. A single FAM20A-like gene is found in some invertebrate chordates (Branchiostoma and Saccoglossus) but it is apparently lost from Ciona. Urchins have two FAM20A genes, one similar to the invertebrate chordates, and the other highly divergent. Insects and nematodes also have just one copy.

Domain Structure

Like other FJ family kinases, FAM20A has a conserved signal peptide but no predicted transmembrane domain. The PKL-type kinase domain is at the C-terminus, with a variable (~200? AA) N-terminus with no known domain and lower sequence conservation than the kinase domain.

Protein Interactions

Human FAM20C interacts with 7 proteins from a single screen [1], all of which are linked to each other, with functions enriched for transcriptional and chromatin regulation. The Drosophila homolog, CG31145 has a single interaction with a dynein light chain, DLC90F. No other family members have known interactors

Functions

Mutations in FAM20C were found to cause bone disorders (Raine Syndrome / Lethal Osteosclerotic Bone Dysplasia) giving rise to abnormally hard and dense bone, usually lethal within hours of birth. Four different non-synonymous changes at 3 positions were found, along with several splice site mutations and a deletion [2, 3, 4]. The disorder is recessive, and while the mutant residues are conserved within vertebrates, they are not conserved within the whole family and do not effect the catalytic residues. Mouse FAM20C (aka DMP4) is selectively expressed in mineralizing bone, and in developing teeth, the differentiation of that odontoblasts, the dentin (mineral)-secreting cells is modulated by FAM20C levels [5, 6].

A FAM20A mutation was also associated with to Amelogenesis Imperfecta, a biomineralization disorder resulting in imperfect tooth enamel [7]. The mutation causes a premature stop of the protein at position 136 and is likely null. A deletion of the FAM20A region in mouse also caused a general postnatal growth retardation [8]

References

1. Vinayagam A, Stelzl U, Foulle R, Plassmann S, Zenkner M, Timm J, Assmus HE, Andrade-Navarro MA, and Wanker EE. A directed protein interaction network for investigating intracellular signal transduction. Sci Signal. 2011 Sep 6;4(189):rs8. DOI:10.1126/scisignal.2001699 |
2. Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, Zackai EH, Al-Gazali LI, Hulskamp G, Kingston HM, Prescott TE, Ion A, Patton MA, Murday V, George A, and Crosby AH. Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet. 2007 Nov;81(5):906-12. DOI:10.1086/522240 |
3. Fradin M, Stoetzel C, Muller J, Koob M, Christmann D, Debry C, Kohler M, Isnard M, Astruc D, Desprez P, Zorres C, Flori E, Dollfus H, and Doray B. Osteosclerotic bone dysplasia in siblings with a Fam20C mutation. Clin Genet. 2011 Aug;80(2):177-83. DOI:10.1111/j.1399-0004.2010.01516.x |
4. Simpson MA, Scheuerle A, Hurst J, Patton MA, Stewart H, and Crosby AH. Mutations in FAM20C also identified in non-lethal osteosclerotic bone dysplasia. Clin Genet. 2009 Mar;75(3):271-6. DOI:10.1111/j.1399-0004.2008.01118.x |
5. Hao J, Narayanan K, Muni T, Ramachandran A, and George A. Dentin matrix protein 4, a novel secretory calcium-binding protein that modulates odontoblast differentiation. J Biol Chem. 2007 May 25;282(21):15357-65. DOI:10.1074/jbc.M701547200 |
6. Wang X, Hao J, Xie Y, Sun Y, Hernandez B, Yamoah AK, Prasad M, Zhu Q, Feng JQ, and Qin C. Expression of FAM20C in the osteogenesis and odontogenesis of mouse. J Histochem Cytochem. 2010 Nov;58(11):957-67. DOI:10.1369/jhc.2010.956565 |
7. O'Sullivan J, Bitu CC, Daly SB, Urquhart JE, Barron MJ, Bhaskar SS, Martelli-Júnior H, dos Santos Neto PE, Mansilla MA, Murray JC, Coletta RD, Black GC, and Dixon MJ. Whole-Exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. Am J Hum Genet. 2011 May 13;88(5):616-20. DOI:10.1016/j.ajhg.2011.04.005 |
8. An C, Ide Y, Nagano-Fujii M, Kitazawa S, Shoji I, and Hotta H. A transgenic mouse line with a 58-kb fragment deletion in chromosome 11E1 that encompasses part of the Fam20a gene and its upstream region shows growth disorder. Kobe J Med Sci. 2010 Feb 23;55(4):E82-92.