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Gene Review

HOXD13  -  homeobox D13

Homo sapiens

Synonyms: BDE, BDSD, HOX4I, Homeobox protein Hox-4I, Homeobox protein Hox-D13, ...
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Disease relevance of HOXD13


Psychiatry related information on HOXD13

  • OBJECTIVES: We sought to clarify the familial relationship between five putative schizophrenia-related personality disorders (schizotypal [SPD], paranoid, schizoid, avoidant, and borderline) and schizophrenia, other nonaffective psychoses, and affective illness [6].
  • Schizotypal and borderline personality disorders (SPD and BPD, respectively) appear to be different at follow-up, yet they are poorly discriminated from each other by current DSM-III symptom criteria [7].
  • This review considers the possible familial relationship of schizotypal and paranoid personality disorders (SPD, PPD) to schizophrenia (SCZ) and affective disorders (AD) [8].
  • The UPD group, although impaired on a spatial recognition task, showed intact discrimination learning and reversal; the MPD and SPD patients showed non-perseverative reversal impairments on both reversal tasks [9].
  • Of these, 98 Caucasians (23 SPD, 52 NSPD and 23 NC) performed a brief neurocognitive battery: Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Visuospatial Working Memory (DOT) and Visual Delayed Recall (Wechsler Memory Scale Visual Reproduction, WMS-VR) [10].

High impact information on HOXD13

  • Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13 [11].
  • Here, it is demonstrated that synpolydactyly, an inherited human abnormality of the hands and feet, is caused by expansions of a polyalanine stretch in the amino-terminal region of HOXD13 [12].
  • Moreover, we found that the mutant HOXD13 with the p.Q317R substitution was unable to transactivate the human EPHA7 promoter [13].
  • Mutations in HOXD13 Underlie Syndactyly Type V and a Novel Brachydactyly-Syndactyly Syndrome [13].
  • In the family with syndactyly type V, we identified a missense mutation in the HOXD13 homeodomain, c.950A-->G (p.Q317R), which leads to substitution of the highly conserved glutamine that is important for DNA-binding specificity and affinity [13].

Chemical compound and disease context of HOXD13

  • In the family with complex brachydactyly and syndactyly, we detected a deletion of 21 bp in the imperfect GCN (where N denotes A, C, G, or T) triplet-containing exon 1 of HOXD13, which results in a polyalanine contraction of seven residues [13].
  • Patients whose platelets are deficient in glycoprotein (GP) Ib, IIb-IIIa (thrombasthenia), or granule substances (storage pool deficiency, SPD) were studied to define further the properties of platelets that mediate platelet adhesion and thrombus formation on subendothelium [14].
  • In six cases we determined MR, plasma aldosterone, and SPD in patients with preeclampsia before and 3 months after delivery [15].
  • In Salmonella typhimurium TA1535 expressing the rat GST5-5 the number of revertants was increased compared to the control strain by CH2Br2, ethylene dibromide (EDB) and 1,2,3,4-diepoxybutane (BDE); in contrast, mutagenicity of 1,2-epoxy-3-(4'-nitro-phenoxy)propane (EPNP) was reduced [16].
  • Two hundred eleven patients consecutively submitted to ERP for upper abdominal symptomatology, with suspected pancreatic disease (SPD; 79 patients) or without (NSPD; 132 subjects), were classified in 3 groups of different ethanol intake: 1 (0-40 g/day), 2 (41-80 g/day), 3 (more than 80 g/day) [17].

Biological context of HOXD13

  • The genomic structure of HOXD13 established in this study consists of two exons that encodes a polypeptide of 335 amino acids [18].
  • Sixty-two meioses from a kindred with 425 individuals were used to map the SPD locus to 2q31 region, approximately 1.7 cM (Lod score = 12.96) centromeric to HOXD8 intragenic marker [1].
  • We report a novel type of mutation in HOXD13, associated in some cases with features of classic SPD and in all cases with a novel foot phenotype [19].
  • Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E [20].
  • The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13 [2].

Anatomical context of HOXD13

  • In two unrelated families, each with a different intragenic deletion in HOXD13, all mutation carriers have a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well [19].
  • In addition, the overexpression of hMTH1, SPD, ITGA11, and COL11A1 was correlated with lymph node metastasis and poor prognosis [21].
  • Elimination of this sump by adding complete dissection of the splenic vein and division of the splenocolic ligament to DSRS (splenopancreatic disconnection, SPD) could preserve portal perfusion, decrease shunt loss of hepatotrophic factor, and improve survival in alcoholic cirrhotics [22].
  • Moreover, our in vitro results reveal that microsomes prepared from human, rat and mouse liver possess the ability to form BDE from BMO [23].
  • Interindividual and interspecies variation in the initial rate of oxidation of 80 microM BMO to BDE was determined using 10 samples of human liver microsomes and single pooled samples from rats and mice [23].

Associations of HOXD13 with chemical compounds

  • Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families [18].
  • Members of the 11, 12, and 13 paralogs do not cooperatively bind DNA with Pbx1a, despite the presence of tryptophan residues N-terminal to the homeodomain in Hoxd-12 and Hoxd-13 [24].
  • Both C-H bond dissociation energies for cyclobutene were measured in the gas phase (BDE = 91.2 +/- 2.3 (allyl) and 112.5 +/- 2.5 (vinyl) kcal mol-1) via a thermodynamic cycle by carrying out proton affinity and electron-binding energy measurements on 1- and 3-cyclobutenyl anions [25].
  • The genetic basis for butadiene carcinogenicity is likely mediated by its metabolite, 1,2:3,4-diepoxybutane (BDE) [23].
  • Oxidation of butadiene to 1,2-epoxy-3-butene (BMO) and further activation to BDE is catalysed by cytochrome P450 (CYP) isozymes [23].

Other interactions of HOXD13

  • A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly [26].
  • An updated order of D2S142-D2S111-(D2S335/D2S333)-D2S326-D2 S1238-SPD- (HOXD8/D2S1244)-(D2S300/D2S138)-D2S148- D2S324- D2S1384-D2S434 [sequence:see text] was deduced from meiotic recombination events [1].
  • We report here a novel NUP98 partner gene, HOXD11, not HOXD13, in a pediatric patient with de novo AML having t(2;11)(q31;p15), using a cDNA panhandle PCR [27].
  • In this report we discuss what is known about HOXA13 and HOXD13 function during GU development, highlighting some of the cellular and molecular mechanisms controlled by these proteins during the GU formation [28].
  • HOXD13, the most 5' gene of the HOXD cluster, encodes a homeodomain transcription factor with important functions in limb patterning and growth [20].

Analytical, diagnostic and therapeutic context of HOXD13


  1. Localization of the syndactyly type II (synpolydactyly) locus to 2q31 region and identification of tight linkage to HOXD8 intragenic marker. Sarfarazi, M., Akarsu, A.N., Sayli, B.S. Hum. Mol. Genet. (1995) [Pubmed]
  2. Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Goodman, F.R., Mundlos, S., Muragaki, Y., Donnai, D., Giovannucci-Uzielli, M.L., Lapi, E., Majewski, F., McGaughran, J., McKeown, C., Reardon, W., Upton, J., Winter, R.M., Olsen, B.R., Scambler, P.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  3. An I47L substitution in the HOXD13 homeodomain causes a novel human limb malformation by producing a selective loss of function. Caronia, G., Goodman, F.R., McKeown, C.M., Scambler, P.J., Zappavigna, V. Development (2003) [Pubmed]
  4. Heterogenous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation. Arai, Y., Kyo, T., Miwa, H., Arai, K., Kamada, N., Kita, K., Ohki, M. Leukemia (2000) [Pubmed]
  5. Sensorineural deafness, abnormal genitalia, synostosis of metacarpals and metatarsals 4 and 5, and mental retardation: description of a second patient and exclusion of HOXD13. Mendioroz, J., Fernández-Toral, J., Suárez, E., López-Grondona, F., Kjaer, K.W., Bermejo, E., Martínez-Frías, M.L. Am. J. Med. Genet. A (2005) [Pubmed]
  6. The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives. Kendler, K.S., McGuire, M., Gruenberg, A.M., O'Hare, A., Spellman, M., Walsh, D. Arch. Gen. Psychiatry (1993) [Pubmed]
  7. Testing DSM-III symptom criteria for schizotypal and borderline personality disorders. McGlashan, T.H. Arch. Gen. Psychiatry (1987) [Pubmed]
  8. Schizotypal and paranoid personality disorder in the relatives of patients with schizophrenia and affective disorders: a review. Webb, C.T., Levinson, D.F. Schizophr. Res. (1993) [Pubmed]
  9. Probabilistic learning and reversal deficits in patients with Parkinson's disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication. Swainson, R., Rogers, R.D., Sahakian, B.J., Summers, B.A., Polkey, C.E., Robbins, T.W. Neuropsychologia. (2000) [Pubmed]
  10. Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups. Minzenberg, M.J., Xu, K., Mitropoulou, V., Harvey, P.D., Finch, T., Flory, J.D., New, A.S., Goldman, D., Siever, L.J. Psychiatr. Genet. (2006) [Pubmed]
  11. Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13. Warren, S.T. Science (1997) [Pubmed]
  12. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Muragaki, Y., Mundlos, S., Upton, J., Olsen, B.R. Science (1996) [Pubmed]
  13. Mutations in HOXD13 Underlie Syndactyly Type V and a Novel Brachydactyly-Syndactyly Syndrome. Zhao, X., Sun, M., Zhao, J., Leyva, J.A., Zhu, H., Yang, W., Zeng, X., Ao, Y., Liu, Q., Liu, G., Lo, W.H., Jabs, E.W., Amzel, L.M., Shan, X., Zhang, X. Am. J. Hum. Genet. (2007) [Pubmed]
  14. Platelet adhesion and thrombus formation on subendothelium in platelets deficient in glycoproteins IIb-IIIa, Ib, and storage granules. Weiss, H.J., Turitto, V.T., Baumgartner, H.R. Blood (1986) [Pubmed]
  15. Mineralocorticoid effector mechanism in preeclampsia. Armanini, D., Zennaro, C.M., Martella, L., Scali, M., Pratesi, C., Grella, P.V., Mantero, F. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  16. Human glutathione S-transferase T1-1 enhances mutagenicity of 1,2-dibromoethane, dibromomethane and 1,2,3,4-diepoxybutane in Salmonella typhimurium. Thier, R., Pemble, S.E., Kramer, H., Taylor, J.B., Guengerich, F.P., Ketterer, B. Carcinogenesis (1996) [Pubmed]
  17. Frequency of pancreatographic changes in subjects with upper abdominal symptoms and its relationship with alcohol intake. Angelini, G., Antolini, G., Bovo, P., Cavallini, G., Fratta Pasini, A., Lavarini, E., Piubello, W., Rigo, L., Scuro, L.A. Int. J. Pancreatol. (1987) [Pubmed]
  18. Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families. Akarsu, A.N., Stoilov, I., Yilmaz, E., Sayli, B.S., Sarfarazi, M. Hum. Mol. Genet. (1996) [Pubmed]
  19. Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families. Goodman, F., Giovannucci-Uzielli, M.L., Hall, C., Reardon, W., Winter, R., Scambler, P. Am. J. Hum. Genet. (1998) [Pubmed]
  20. Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. Johnson, D., Kan, S.H., Oldridge, M., Trembath, R.C., Roche, P., Esnouf, R.M., Giele, H., Wilkie, A.O. Am. J. Hum. Genet. (2003) [Pubmed]
  21. Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer. Chong, I.W., Chang, M.Y., Chang, H.C., Yu, Y.P., Sheu, C.C., Tsai, J.R., Hung, J.Y., Chou, S.H., Tsai, M.S., Hwang, J.J., Lin, S.R. Oncol. Rep. (2006) [Pubmed]
  22. Splenopancreatic disconnection. Improved selectivity of distal splenorenal shunt. Warren, W.D., Millikan, W.J., Henderson, J.M., Abu-Elmagd, K.M., Galloway, J.R., Shires, G.T., Richards, W.O., Salam, A.A., Kutner, M.H. Ann. Surg. (1986) [Pubmed]
  23. Oxidation of 1,2-epoxy-3-butene to 1,2:3,4-diepoxybutane by cDNA-expressed human cytochromes P450 2E1 and 3A4 and human, mouse and rat liver microsomes. Seaton, M.J., Follansbee, M.H., Bond, J.A. Carcinogenesis (1995) [Pubmed]
  24. The Abd-B-like Hox homeodomain proteins can be subdivided by the ability to form complexes with Pbx1a on a novel DNA target. Shen, W.F., Rozenfeld, S., Lawrence, H.J., Largman, C. J. Biol. Chem. (1997) [Pubmed]
  25. Cycloalkane and cycloalkene C-h bond dissociation energies. Tian, Z., Fattahi, A., Lis, L., Kass, S.R. J. Am. Chem. Soc. (2006) [Pubmed]
  26. A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly. Goodman, F.R., Majewski, F., Collins, A.L., Scambler, P.J. Am. J. Hum. Genet. (2002) [Pubmed]
  27. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Taketani, T., Taki, T., Shibuya, N., Ito, E., Kitazawa, J., Terui, K., Hayashi, Y. Cancer Res. (2002) [Pubmed]
  28. Genitourinary functions of Hoxa13 and Hoxd13. Scott, V., Morgan, E.A., Stadler, H.S. J. Biochem. (2005) [Pubmed]
  29. Frequent increase of DNA copy number in the 2q24 chromosomal region and its association with a poor clinical outcome in hepatoblastoma: cytogenetic and comparative genomic hybridization analysis. Kumon, K., Kobayashi, H., Namiki, T., Tsunematsu, Y., Miyauchi, J., Kikuta, A., Horikoshi, Y., Komada, Y., Hatae, Y., Eguchi, H., Kaneko, Y. Jpn. J. Cancer Res. (2001) [Pubmed]
  30. A simple method for generating full length cDNA from low abundance partial genomic clones. Wang, Y., Fugaro, J.M., Siddiq, F., Goparaju, C.M., Lonardo, F., Wali, A., Lechner, J.F., Pass, H.I. BMC Mol. Biol. (2000) [Pubmed]
  31. Sonic hedgehog, BMP4, and Hox genes in the development of anorectal malformations in Ethylenethiourea-exposed fetal rats. Mandhan, P., Quan, Q.B., Beasley, S., Sullivan, M. J. Pediatr. Surg. (2006) [Pubmed]
  32. Failure of enzyme encapsulation to prevent sensitization of workers in the dry bleach industry. Liss, G.M., Kominsky, J.R., Gallagher, J.S., Melius, J., Brooks, S.M., Bernstein, I.L. J. Allergy Clin. Immunol. (1984) [Pubmed]
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