Homeobox A1 Explained

Homeobox protein Hox-A1 is a protein that in humans is encoded by the HOXA1 gene.^{[1] [2] [3]}

Gene

Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region.^[4]

Function

In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and cellular differentiation. The homeobox protein Hox-A1 may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development.^[4]

Clinical significance

A common polymorphism in the HOXA1 gene is associated with a susceptibility to autism spectrum disorder, with individuals possessing these gene variant have an approximately doubled risk of developing the disorder.^[5] Studies on knockout mice have indicated that the gene can alter embryological development of the brain stem (specifically the facial and superior olivary nuclei), as well as induce several other physical changes such as in ear shape.^[6] Both of these sets of changes can also be seen in patients with autism.

Other HOXA1 mutations are associated with Bosley-Salih-Alorainy syndrome (BSAS) or the Athabaskan brainstem dysgenesis syndrome (ABDS).^[7]

Regulation

The HOXA1 gene is repressed by the microRNA miR-10a.^[8]

See also

• Homeobox

Further reading

• Chariot A, Moreau L, Senterre G, Sobel ME, Castronovo V . Retinoic acid induces three newly cloned HOXA1 transcripts in MCF7 breast cancer cells . Biochemical and Biophysical Research Communications . 215 . 2 . 713–20 . October 1995 . 7488013 . 10.1006/bbrc.1995.2522 . 2268/3751 . free .
• Studer M, Gavalas A, Marshall H, Ariza-McNaughton L, Rijli FM, Chambon P, Krumlauf R . Genetic interactions between Hoxa1 and Hoxb1 reveal new roles in regulation of early hindbrain patterning . Development . 125 . 6 . 1025–36 . March 1998 . 10.1242/dev.125.6.1025 . 9463349 . free .
• Green NC, Rambaldi I, Teakles J, Featherstone MS . A conserved C-terminal domain in PBX increases DNA binding by the PBX homeodomain and is not a primary site of contact for the YPWM motif of HOXA1 . The Journal of Biological Chemistry . 273 . 21 . 13273–9 . May 1998 . 9582372 . 10.1074/jbc.273.21.13273 . free .
• Barrow JR, Capecchi MR . Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants . Development . 126 . 22 . 5011–26 . November 1999 . 10.1242/dev.126.22.5011 . 10529419 .
• Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, Helfrich B, Bunn P, Roche J, Brambilla E, Rosell R, Gemmill RM, Drabkin HA . Altered HOX and WNT7A expression in human lung cancer . Proceedings of the National Academy of Sciences of the United States of America . 97 . 23 . 12776–81 . November 2000 . 11070089 . 18840 . 10.1073/pnas.97.23.12776 . 2000PNAS...9712776C . free .
• Li J, Tabor HK, Nguyen L, Gleason C, Lotspeich LJ, Spiker D, Risch N, Myers RM . Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families . American Journal of Medical Genetics . 114 . 1 . 24–30 . Jan 2002 . 11840501 . 10.1002/ajmg.1618 .
• Kosaki K, Kosaki R, Suzuki T, Yoshihashi H, Takahashi T, Sasaki K, Tomita M, McGinnis W, Matsuo N . Complete mutation analysis panel of the 39 human HOX genes . Teratology . 65 . 2 . 50–62 . February 2002 . 11857506 . 10.1002/tera.10009 .
• Devlin B, Bennett P, Cook EH, Dawson G, Gonen D, Grigorenko EL, McMahon W, Pauls D, Smith M, Spence MA, Schellenberg GD . No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network . American Journal of Medical Genetics . 114 . 6 . 667–72 . August 2002 . 12210285 . 10.1002/ajmg.10603 . 23795745 .
• Rodier PM . Converging evidence for brain stem injury in autism . Development and Psychopathology . 14 . 3 . 537–57 . 2003 . 12349873 . 10.1017/s0954579402003085 . 19453261 .
• Zhang X, Zhu T, Chen Y, Mertani HC, Lee KO, Lobie PE . Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene . The Journal of Biological Chemistry . 278 . 9 . 7580–90 . February 2003 . 12482855 . 10.1074/jbc.M212050200 . free .
• Conciatori M, Stodgell CJ, Hyman SL, O'Bara M, Militerni R, Bravaccio C, Trillo S, Montecchi F, Schneider C, Melmed R, Elia M, Crawford L, Spence SJ, Muscarella L, Guarnieri V, D'Agruma L, Quattrone A, Zelante L, Rabinowitz D, Pascucci T, Puglisi-Allegra S, Reichelt KL, Rodier PM, Persico AM . Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism . Biological Psychiatry . 55 . 4 . 413–9 . February 2004 . 14960295 . 10.1016/j.biopsych.2003.10.005 . 6903399 .
• Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ, Oystreck DT, Chan WM, Andrews C, Erickson RP, Engle EC . Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development . Nature Genetics . 37 . 10 . 1035–7 . October 2005 . 16155570 . 10.1038/ng1636 . 12062207 .

Notes and References

1. Hong YS, Kim SY, Bhattacharya A, Pratt DR, Hong WK, Tainsky MA . Structure and function of the HOX A1 human homeobox gene cDNA . Gene . 159 . 2 . 209–14 . July 1995 . 7622051 . 10.1016/0378-1119(95)92712-G .
2. Apiou F, Flagiello D, Cillo C, Malfoy B, Poupon MF, Dutrillaux B . Fine mapping of human HOX gene clusters . Cytogenetics and Cell Genetics . 73 . 1–2 . 114–5 . 1996 . 8646877 . 10.1159/000134320 .
3. McAlpine PJ, Shows TB . Nomenclature for human homeobox genes . Genomics . 7 . 3 . 460 . July 1990 . 1973146 . 10.1016/0888-7543(90)90186-X .
4. Web site: Entrez Gene: HOXA1 homeobox A1.
5. Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM . Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders . Teratology . 62 . 6 . 393–405 . December 2000 . 11091361 . 10.1002/1096-9926(200012)62:6<393::AID-TERA6>3.0.CO;2-V . free .
6. Rodier. Patricia. The Early Origins of Autism. Scientific American. February 2000. 282. 2. 56–63. 10.1038/scientificamerican0200-56. 10710787. 2000SciAm.282b..56R.
7. Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP . The clinical spectrum of homozygous HOXA1 mutations . American Journal of Medical Genetics Part A . 146A . 10 . 1235–40 . May 2008 . 18412118 . 3517166 . 10.1002/ajmg.a.32262 .
8. Garzon R, Pichiorri F, Palumbo T, Iuliano R, Cimmino A, Aqeilan R, Volinia S, Bhatt D, Alder H, Marcucci G, Calin GA, Liu CG, Bloomfield CD, Andreeff M, Croce CM . MicroRNA fingerprints during human megakaryocytopoiesis . Proceedings of the National Academy of Sciences of the United States of America . 103 . 13 . 5078–83 . March 2006 . 16549775 . 1458797 . 10.1073/pnas.0600587103 . 2006PNAS..103.5078G . free .