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Gene Review

BHLHE41  -  basic helix-loop-helix family, member e41

Homo sapiens

Synonyms: BHLHB3, Class B basic helix-loop-helix protein 3, Class E basic helix-loop-helix protein 41, DEC2, Differentially expressed in chondrocytes protein 2, ...
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Disease relevance of BHLHB3

  • In the present study, we found that hypoxia or CoCl(2) enhanced the mRNA expression of DEC2, as well as DEC1, within 24 h in chondrogenic ATDC5, 293T, and HeLa cells [1].
  • Without exceptions, DEC1 was markedly higher in the carcinomas, whereas the opposite was true with DEC2 [2].
  • Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method [3].
  • METHODS: A random sample of patients with early RA, for whom sequential hand radiographs and Sharp scores were available, was selected from the National Data Bank for Rheumatic Diseases [4].
  • METHODS: Wrist/hand radiographs of 25 patients with polyarthritis obtained at first observation and then yearly for 4-5 years were assessed independently by 2 pediatric rheumatologists according to the Sharp and Larsen methods [5].

High impact information on BHLHB3

  • Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup [6].
  • OBJECTIVE: To investigate the applicability of the Sharp and Larsen scoring methods for radiographic damage in juvenile idiopathic arthritis (JIA) [5].
  • Additional end points included scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks [7].
  • Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was -0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001) [8].
  • The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]) [9].

Biological context of BHLHB3

  • Basic helix-loop-helix transcription factors, BHLHB2 and BHLHB3; their gene expressions are regulated by multiple extracellular stimuli [10].
  • Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes [1].
  • Transcription factors DEC1 and DEC2 also play pivotal roles in multiple signaling pathways impacting various biological processes including development, cell differentiation, cell death, and oncogenesis [11].
  • The ascorbate binding site was recently identified as being close to the gamma-heme edge [Sharp, K. H., Mewies, M., Moody, P. C. E., and Raven, E. L. (2003)Nat. Struct. Biol. 10, 303-307] [12].
  • Crystallographic data (to 1.8 A) for the R172A variant indicate that the molecular structure of the proposed [Sharp, K. H., et al. (2004) Biochemistry 43, 8644-8651] proton transfer pathway from the ascorbate to the heme is conserved, which accounts for the residual activity [13].

Anatomical context of BHLHB3

  • We believe that a normal relationship between the acetabulum and the femoral head was established when there was an acetabular index of <20 degrees or a Sharp angle of <42 degrees, a center-edge angle of >20 degrees, and an intact Shenton's line [14].
  • The following values were assessed: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-CCP, Disease Activity Score 28 (DAS 28), Modified Health Assessment Questionnaire score (M-HAQ) and simplified radiologic score of Sharp/Van der Heijde (SENS: simple erosion narrowing score) [15].
  • BACKGROUND: Problems attributed to the accumulation of wax (cerumen) are one of the most common reasons for people to present to their general practitioners with ear trouble (Sharp 1990) [16].
  • Radial Artery Harvest Using the Sharp Scissors Method for Patients with Pathological Findings on Allen's Test [17].

Associations of BHLHB3 with chemical compounds

  • During the course of a one-hybrid screen for transcription factors that bind to regulatory domains of the M1 muscarinic acetylcholine receptor gene, we isolated the bHLH transcription factor SHARP-1 [18].
  • In stable transfectants, tetracycline-induced expression of DEC1 caused proportional decreases in the expression of DEC2 [2].
  • RESULTS: At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group [19].
  • Radiographic progression (measured using modified Sharp Score) after one year of treatment was lower in subjects treated with both etanercept and MTX compared with subjects treated with either agent used alone, and this pattern was similar in both age groups [20].
  • OBJECTIVE: To compare the bioavailability of two potassic losartan immediate release tablet (50 mg) formulations (Losartan from Laboratórios Cristália Ltd., Brazil, as a test formulation and Cozaar from Merck Sharp & Dohme Farmacêutica Ltd., Brazil, as a reference formulation) in 25 volunteers of both sexes [21].

Regulatory relationships of BHLHB3

  • Co-transfection with DEC1 repressed the activity of a DEC2 promoter reporter by as much as 90% [2].

Other interactions of BHLHB3

  • Both the BHLHB2 and BHLHB3 genes are widely expressed in both embryonic and adult tissues [10].
  • A total radiographic damage score (TDS; by the Sharp/van der Heijde method) was used to quantify RA severity at baseline and after 4 years of followup [22].
  • Duration of morning stiffness, number of swollen joints, serum rheumatoid factor (RF), erythrocyte sedimentation rate, C-reactive protein (CRP) level, and radiographs of hands and feet (Sharp/van der Heijde score) were assessed at each follow-up [23].
  • Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison) [24].

Analytical, diagnostic and therapeutic context of BHLHB3

  • Chromosome segment-specific cDNA array analysis of 29 expressed sequences within the whole interval between D12S1617 and sts-N38796 indicated overexpression of four ESTs, two corresponding to DEC2 and PPFIBP1, and two to ESTs with unknown function [25].
  • Randomized trial on two types of thermoplastic masks for patient immobilization during radiation therapy for head-and-neck cancer: In regard to Sharp et al. (Int J Radiat Oncol Biol Phys 2005;61:250-256) [26].
  • Methods: Sharp microelectrodes were used for intracellular recording and stimulation of cortical neurons in rat brain slices [27].
  • The pharmacokinetic and relative bioavailability studies of 20-mg enalapril tablets, the test product manufactured by Biolab, Thailand compared to the reference product (Merck Sharp & Dohme, USA) was conducted in 14 healthy Thai male volunteers following a single dose, two-period, crossover design [28].


  1. Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. Miyazaki, K., Kawamoto, T., Tanimoto, K., Nishiyama, M., Honda, H., Kato, Y. J. Biol. Chem. (2002) [Pubmed]
  2. DEC1 negatively regulates the expression of DEC2 through binding to the E-box in the proximal promoter. Li, Y., Xie, M., Song, X., Gragen, S., Sachdeva, K., Wan, Y., Yan, B. J. Biol. Chem. (2003) [Pubmed]
  3. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. van Gaalen, F.A., van Aken, J., Huizinga, T.W., Schreuder, G.M., Breedveld, F.C., Zanelli, E., van Venrooij, W.J., Verweij, C.L., Toes, R.E., de Vries, R.R. Arthritis Rheum. (2004) [Pubmed]
  4. Performance of an automated computer-based scoring method to assess joint space narrowing in rheumatoid arthritis: a longitudinal study. Finckh, A., de Pablo, P., Katz, J.N., Neumann, G., Lu, Y., Wolfe, F., Duryea, J. Arthritis Rheum. (2006) [Pubmed]
  5. Use of the sharp and larsen scoring methods in the assessment of radiographic progression in juvenile idiopathic arthritis. Rossi, F., Di Dia, F., Galip??, O., Pistorio, A., Valle, M., Magni-Manzoni, S., Ruperto, N., Tom??, P., Martini, A., Ravelli, A. Arthritis Rheum. (2006) [Pubmed]
  6. A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for rheumatoid arthritis structural severity. Gourraud, P.A., Boyer, J.F., Barnetche, T., Abbal, M., Cambon-Thomsen, A., Cantagrel, A., Constantin, A. Arthritis Rheum. (2006) [Pubmed]
  7. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Cohen, S.B., Emery, P., Greenwald, M.W., Dougados, M., Furie, R.A., Genovese, M.C., Keystone, E.C., Loveless, J.E., Burmester, G.R., Cravets, M.W., Hessey, E.W., Shaw, T., Totoritis, M.C. Arthritis Rheum. (2006) [Pubmed]
  8. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Mease, P.J., Kivitz, A.J., Burch, F.X., Siegel, E.L., Cohen, S.B., Ory, P., Salonen, D., Rubenstein, J., Sharp, J.T., Tsuji, W. Arthritis Rheum. (2004) [Pubmed]
  9. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Keystone, E.C., Kavanaugh, A.F., Sharp, J.T., Tannenbaum, H., Hua, Y., Teoh, L.S., Fischkoff, S.A., Chartash, E.K. Arthritis Rheum. (2004) [Pubmed]
  10. Basic helix-loop-helix transcription factors, BHLHB2 and BHLHB3; their gene expressions are regulated by multiple extracellular stimuli. Yamada, K., Miyamoto, K. Front. Biosci. (2005) [Pubmed]
  11. UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway. Li, Y., Bi, Z., Yan, B., Wan, Y. Int. J. Mol. Med. (2006) [Pubmed]
  12. Crystal structure of the ascorbate peroxidase-salicylhydroxamic acid complex. Sharp, K.H., Moody, P.C., Brown, K.A., Raven, E.L. Biochemistry (2004) [Pubmed]
  13. Interaction of ascorbate peroxidase with substrates: a mechanistic and structural analysis. Macdonald, I.K., Badyal, S.K., Ghamsari, L., Moody, P.C., Raven, E.L. Biochemistry (2006) [Pubmed]
  14. Surgical correction of residual hip dysplasia in two pediatric age-groups. Lalonde, F.D., Frick, S.L., Wenger, D.R. The Journal of bone and joint surgery. American volume. (2002) [Pubmed]
  15. Anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: relation with disease aggressiveness. del Val del Amo, N., Ibanez Bosch, R., Fito Manteca, C., Gutierrez Polo, R., Loza Cortina, E. Clin. Exp. Rheumatol. (2006) [Pubmed]
  16. Ear drops for the removal of ear wax. Burton, M.J., Dorée, C.J. Cochrane database of systematic reviews (Online) (2003) [Pubmed]
  17. Radial Artery Harvest Using the Sharp Scissors Method for Patients with Pathological Findings on Allen's Test. Hata, M., Sezai, A., Niino, T., Yoda, M., Wakui, S., Soeda, M., Nohata, I., Shiono, M., Minami, K. Surg. Today (2006) [Pubmed]
  18. The basic helix-loop-helix protein, sharp-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism. Garriga-Canut, M., Roopra, A., Buckley, N.J. J. Biol. Chem. (2001) [Pubmed]
  19. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Landewé, R.B., Boers, M., Verhoeven, A.C., Westhovens, R., van de Laar, M.A., Markusse, H.M., van Denderen, J.C., Westedt, M.L., Peeters, A.J., Dijkmans, B.A., Jacobs, P., Boonen, A., van der Heijde, D.M., van der Linden, S. Arthritis Rheum. (2002) [Pubmed]
  20. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. Bathon, J.M., Fleischmann, R.M., Van der Heijde, D., Tesser, J.R., Peloso, P.M., Chon, Y., White, B. J. Rheumatol. (2006) [Pubmed]
  21. Comparative bioavailability of two losartan formulations in healthy human volunteers after a single dose administration. Oliveira, C.H., Medeiros Silva, R., Santagada, V., Caliendo, G., Perissutti, E., Prado Galuppo, M., Marcondes Rezende, V., Barrientos-Astigarraga, R.E., Duarte Mendes, G., De Nucci, G. International journal of clinical pharmacology and therapeutics. (2006) [Pubmed]
  22. Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study. Constantin, A., Lauwers-Cancès, V., Navaux, F., Abbal, M., van Meerwijk, J., Mazières, B., Cambon-Thomsen, A., Cantagrel, A. Arthritis Rheum. (2002) [Pubmed]
  23. Synovial membrane enhancement and bone erosion by magnetic resonance imaging for prediction of radiologic progression in patients with early rheumatoid arthritis. Tanaka, N., Sakahashi, H., Ishii, S., Sato, E., Hirose, K., Ishima, T. Rheumatol. Int. (2005) [Pubmed]
  24. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. St Clair, E.W., van der Heijde, D.M., Smolen, J.S., Maini, R.N., Bathon, J.M., Emery, P., Keystone, E., Schiff, M., Kalden, J.R., Wang, B., Dewoody, K., Weiss, R., Baker, D. Arthritis Rheum. (2004) [Pubmed]
  25. Detailed genomic mapping and expression analyses of 12p amplifications in pancreatic carcinomas reveal a 3.5-Mb target region for amplification. Heidenblad, M., Jonson, T., Mahlamäki, E.H., Gorunova, L., Karhu, R., Johansson, B., Höglund, M. Genes Chromosomes Cancer (2002) [Pubmed]
  26. Randomized trial on two types of thermoplastic masks for patient immobilization during radiation therapy for head-and-neck cancer: In regard to Sharp et al. (Int J Radiat Oncol Biol Phys 2005;61:250-256). Roques, T., Dagless, M., Tomes, J. Int. J. Radiat. Oncol. Biol. Phys. (2005) [Pubmed]
  27. Fast oscillations trigger bursts of action potentials in neocortical neurons in vitro: A quasi-white-noise analysis study. Schindler, K.A., Goodman, P.H., Wieser, H.G., Douglas, R.J. Brain Res. (2006) [Pubmed]
  28. Relative bioavailability study of 20-mg enalapril tablets in healthy male volunteers. Lohitnavy, O., Lohitnavy, M., Polnok, S., Taytiwat, P. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. (2003) [Pubmed]
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