PHF6 explained

PHD finger protein 6 is a protein that in humans is encoded by the PHF6 gene.^{[1] [2]}

This gene is a member of the plant homeodomain (PHD)-like finger (PHF) family. It encodes a protein with two atypical PHD-type zinc finger domains, indicating a potential role in transcriptional regulation, that localizes to the nucleolus.

Mutations

Mutations affecting the coding region of this gene or the splicing of the transcript have been associated with Börjeson-Forssman-Lehmann syndrome (BFLS), a disorder characterized by mental retardation, epilepsy, hypogonadism, hypometabolism, obesity, swelling of subcutaneous tissue of the face, narrow palpebral fissures, and large ears. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

The PHF6 gene in humans is also frequently mutated in human hematological malignancies, including T-cell acute lymphoblastic Leukemia (T-ALL)^[3] and Acute Myeloid Leukemia (AML)^[4] and at least two BFLS patients have developed leukemia or lymphoma.^[5] PHF6 has been shown to be important for the regulation of blood stem and progenitor cells^{[6] [7] [8] [9]} and loss of PHF6 protein synergizes with over-expression of the TLX3 protein to cause lymphoid neoplasms.

Further reading

• Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O . Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 8 . 2 . 85–95 . April 2001 . 11347906 . 10.1093/dnares/8.2.85 . free .
• Baumstark A, Lower KM, Sinkus A, Andriuskeviciute I, Jurkeniene L, Gécz J, Just W . Novel PHF6 mutation p.D333del causes Börjeson-Forssman-Lehmann syndrome . Journal of Medical Genetics . 40 . 4 . 50e–50 . April 2003 . 12676923 . 1735415 . 10.1136/jmg.40.4.e50 .
• Dattani MT . Borjeson-Forssman-Lehmann syndrome: a novel pituitary phenotype due to mutation in a novel gene . Journal of Pediatric Endocrinology & Metabolism . 16 . 9 . 1207–9 . December 2003 . 14714741 . 10.1515/jpem.2003.16.9.1207 . 45542882 .
• Birrell G, Lampe A, Richmond S, Bruce SN, Gécz J, Lower K, Wright M, Cheetham TD . 6 . Borjeson-Forssman-Lehmann syndrome and multiple pituitary hormone deficiency . Journal of Pediatric Endocrinology & Metabolism . 16 . 9 . 1295–300 . December 2003 . 14714754 . 10.1515/jpem.2003.16.9.1295 . 10327867 .
• Turner G, Lower KM, White SM, Delatycki M, Lampe AK, Wright M, Smith JC, Kerr B, Schelley S, Hoyme HE, De Vries BB, Kleefstra T, Grompe M, Cox B, Gecz J, Partington M . 6 . The clinical picture of the Börjeson-Forssman-Lehmann syndrome in males and heterozygous females with PHF6 mutations . Clinical Genetics . 65 . 3 . 226–32 . March 2004 . 14756673 . 10.1111/j.0009-9163.2004.00215.x . 24602739 .
• Lower KM, Solders G, Bondeson ML, Nelson J, Brun A, Crawford J, Malm G, Börjeson M, Turner G, Partington M, Gécz J . 7327686 . 6 . 1024C> T (R342X) is a recurrent PHF6 mutation also found in the original Börjeson-Forssman-Lehmann syndrome family . European Journal of Human Genetics . 12 . 10 . 787–9 . October 2004 . 15241480 . 10.1038/sj.ejhg.5201228 .
• Vallée D, Chevrier E, Graham GE, Lazzaro MA, Lavigne PA, Hunter AG, Picketts DJ . A novel PHF6 mutation results in enhanced exon skipping and mild Börjeson-Forssman-Lehmann syndrome . Journal of Medical Genetics . 41 . 10 . 778–83 . October 2004 . 15466013 . 1735599 . 10.1136/jmg.2004.020370 .
• Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M . 4344740 . Nucleolar proteome dynamics . Nature . 433 . 7021 . 77–83 . January 2005 . 15635413 . 10.1038/nature03207 . 2005Natur.433...77A .
• Crawford J, Lower KM, Hennekam RC, Van Esch H, Mégarbané A, Lynch SA, Turner G, Gécz J . 6 . Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient . Journal of Medical Genetics . 43 . 3 . 238–43 . March 2006 . 15994862 . 2563250 . 10.1136/jmg.2005.033084 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . 7827573 . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . free .

Notes and References

1. Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, Schelley S, Hoyme HE, White SM, Delatycki MB, Lampe AK, Clayton-Smith J, Stewart H, van Ravenswaay CM, de Vries BB, Cox B, Grompe M, Ross S, Thomas P, Mulley JC, Gécz J . 10274037 . 6 . Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome . Nature Genetics . 32 . 4 . 661–5 . December 2002 . 12415272 . 10.1038/ng1040 .
2. Web site: Entrez Gene: PHF6 PHD finger protein 6.
3. Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, Taghon T, Zuurbier L, Cauwelier B, Harrison CJ, Schwab C, Pisecker M, Strehl S, Langerak AW, Gecz J, Sonneveld E, Pieters R, Paietta E, Rowe JM, Wiernik PH, Benoit Y, Soulier J, Poppe B, Yao X, Cordon-Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando A . 6 . PHF6 mutations in T-cell acute lymphoblastic leukemia . Nature Genetics . 42 . 4 . 338–42 . April 2010 . 20228800 . 2847364 . 10.1038/ng.542 .
4. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, Nicolas C, Payer AR, Fernandez HF, Tallman MS, Paietta E, Melnick A, Vandenberghe P, Speleman F, Aifantis I, Cools J, Levine R, Ferrando A . 6 . PHF6 mutations in adult acute myeloid leukemia . Leukemia . 25 . 1 . 130–4 . January 2011 . 21030981 . 3878659 . 10.1038/leu.2010.247 .
5. Chao MM, Todd MA, Kontny U, Neas K, Sullivan MJ, Hunter AG, Picketts DJ, Kratz CP . 6 . T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6 . Pediatric Blood & Cancer . 55 . 4 . 722–4 . October 2010 . 20806366 . 2933084 . 10.1002/pbc.22574 .
6. Wendorff AA, Quinn SA, Rashkovan M, Madubata CJ, Ambesi-Impiombato A, Litzow MR, Tallman MS, Paietta E, Paganin M, Basso G, Gastier-Foster JM, Loh ML, Rabadan R, Van Vlierberghe P, Ferrando AA . 6 . Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL . Cancer Discovery . 9 . 3 . 436–451 . March 2019 . 30567843 . 10.1158/2159-8290.CD-18-1005 . 6425751 .
7. McRae HM, Garnham AL, Hu Y, Witkowski MT, Corbett MA, Dixon MP, May RE, Sheikh BN, Chiang W, Kueh AJ, Nguyen TA, Man K, Gloury R, Aubrey BJ, Policheni A, Di Rago L, Alexander WS, Gray DH, Strasser A, Hawkins ED, Wilcox S, Gécz J, Kallies A, McCormack MP, Smyth GK, Voss AK, Thomas T . 6 . PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia . Blood . 133 . 16 . 1729–1741 . April 2019 . 30755422 . 6695515 . 10.1182/blood-2018-07-860726 .
8. Miyagi S, Sroczynska P, Kato Y, Nakajima-Takagi Y, Oshima M, Rizq O, Takayama N, Saraya A, Mizuno S, Sugiyama F, Takahashi S, Matsuzaki Y, Christensen J, Helin K, Iwama A . 6 . The chromatin-binding protein Phf6 restricts the self-renewal of hematopoietic stem cells . Blood . 133 . 23 . 2495–2506 . June 2019 . 30917958 . 10.1182/blood.2019000468 . free .
9. Hsu YC, Chen TC, Lin CC, Yuan CT, Hsu CL, Hou HA, Kao CJ, Chuang PH, Chen YR, Chou WC, Tien HF . 6 . Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials . Blood Advances . 3 . 15 . 2355–2367 . August 2019 . 31395598 . 6693005 . 10.1182/bloodadvances.2019000391 .