Genetic Separation of the Human Lacritin Gene (“LACRT”) and Triple A (Allgrove) Syndrome on 12Q13

  • Rajesh Kumar
  • Angela Huebner
  • Gordon W. Laurie
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 506)


Molecular mechanisms underlying the pathogenic decline of secretory output by the main lacrimal gland, and subsequently dry eye, are potentially multiple. Inflammatory expansion of B and T lymphocytes can lead to loss of lacrimal acini.1 Curiously, however, acinar volume loss often appears insufficient relative to the theoretical overcapacity of the main lacrimal gland. Estimates suggest a potential secretory output up to 10-fold greater than required to maintain a normal aqueous tear film layer.2,3 Other mechanisms, therefore, warrant attention, such as aberrant secretion of one or several common cytokines that may directly or indirectly alter lacrimal acinar cell function and/or lead to a decline in neural innervation.4 Novel autocrine/paracrine factor(s) released by lacrimal acinar cells into the tear film may be required for the health of the lacrimal secretory machinery, ductal system and corneal epithelium.5 The periacinar basement membrane is also required for normal secretory function,6 in part via BM180 whose apparent synergy with laminin-1 promotes stimulated tear secretion.7,8 Alteration of each factor, together or independent of hormonal changes, could contribute to decreased secretory capacity.


Contact Lens Contact Lens Wear Lens Surface Microbial Keratitis Silicone Hydrogel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M.A. Lemp, Dry eye syndromes: treatment and clinical trials, Adv Exp Med Biol. 350:553 (1994).CrossRefPubMedGoogle Scholar
  2. 2.
    F.J. Holly, Tear film physiology, Int Ophthalmol Clin. 27:2 (1987).CrossRefPubMedGoogle Scholar
  3. 3.
    C. Snyder and R.J. Fullard, Clinical profiles of non-dry eye patients and correlations with tear protein levels, Int Ophthalmol. 15:383 (1991).CrossRefPubMedGoogle Scholar
  4. 4.
    D.A. Sullivan, L.A. Wickham, E.M. Rocha, K.L. Krenzer, B.D. Sullivan, R. Steagall, J.M. Cermak, M.R. Dana, M.D. Ullman, E.H. Sato, J. Gao, F.J. Rocha, M. Ono, L.A. Silveira, R.W. Lambert, R.S. Kelleher, D.B. Tolls, and I. Toda, Androgens and dry eye in Sj0gren’s syndrome. Ann NY Acad Sci. 876:312 (1999).CrossRefPubMedGoogle Scholar
  5. 5.
    S. Sanghi, R. Kumar, A. Lumsden, D. Dickinson, V. Klepeis, V. Trinkaus-Randall, H.F. Frierson, and G.W. Laurie, cDNA and genomic cloning of “lacritin,” a novel secretion enhancing factor from the human lacrimal gland, J Mol Biol. 310:127 (2001).CrossRefPubMedGoogle Scholar
  6. 6.
    L. Chen, J.D. Glass, S.C. Walton, and G.W. Laurie, Role of laminin-1, collagen IV, and an autocrine factor(s) in regulated secretion by lacrimal acinar cells, Am J Physiol. 275:C278 (1998).Google Scholar
  7. 7.
    G.W. Laurie, P.J. Ciclitira, H.J. Ellis, and G. Pogany, Immunological and partial sequence identity of mouse BM180 with wheat alpha-gliadin, Biochem Biophys Res Commun. 217:10 (1995).CrossRefPubMedGoogle Scholar
  8. 8.
    G.W. Laurie, J.D. Glass, R.A. Ogle, C.M. Stone, J.R. Sluss, and L. Chen, “BM180”: a novel basement membrane protein with a role in stimulus-secretion coupling by lacrimal acinar cells, Am J Physiol. 270:C1743 (1996).Google Scholar
  9. 9.
    M. Gazarian, C.T. Cowell, M. Bonney, and W.G. Grigor, The “4A” syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurologic abnormalities, Eur J Pediatr. 154:18 (1995).CrossRefPubMedGoogle Scholar
  10. 10.
    M.L. Chu, D. Berlin, and F.B. Axelrod, Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests, J Pediatrics. 129:156 (1996).CrossRefGoogle Scholar
  11. 11.
    A. Huebner, L.L. Elias, and A.J. Clark, ACTH resistance syndromes, J Pediatr Endocrinol Metab. 12 (Suppl 1):277 (1999).PubMedGoogle Scholar
  12. 12.
    P.S.J. Moore, R.M. Crouch, Y.S. Perry, E.P. Shuckett, and J.S.D. Winter, Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima, Clin Endocrinol. 34:107 (1991).CrossRefGoogle Scholar
  13. 13.
    A. Weber, T.F. Wienker, M. Jung, D. Easton, H.J. Dean, C. Heinrichs, A. Reis, and A.J.L. Clark, Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster, Hum Mol Genet. 5: 2061 (1996).CrossRefPubMedGoogle Scholar
  14. 14.
    C.A. Stratakis, J.-P. Lin, E. Pras, O.M. Rennert, C.J. Bourdony, and W.-Y. Chan, Segregation of Allgrove (triple-A) syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers, Proc Assoc Am Phys. 109:478 (1997).PubMedGoogle Scholar
  15. 15.
    K. Handschug, S. Sperling, S.J.K. Yoon, S. Hennig, A.J.L. Clark, and A. Huebner, Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene, Hum. Mol. Genet. 10: 283 (2001).CrossRefPubMedGoogle Scholar
  16. 16.
    H. Lee, E. Choi, Y. Seomun, K. Montgomery, A. Huebner, E. Lee, S. Lau, C.-K. Joo, R. Kucherlapati, and K.S.-J. Yoon, High-resolution transcript map of the region spanning D12S1629 and D12S312 at chromosome 12q13: triple A syndrome-linked region, Genome Res. 10:1561 (2000).CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    A. Tullio-Pelet, R. Salomon, S. Hadj-Rabia, C. Mugnier, M.H. de Laet, B. Chaouachi, F. Bakiri, P. Brottier, L. Cattolico, C. Penet, M. Begeot, D. Naville, M. Nicolino, J.L. Chaussain, J. Weissenbach, A. Munnich, and S. Lyonnet, Mutant WD-repeat protein in triple-A syndrome, Nat Genet. 26:332 (2000).CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic/Plenum Publishers 2002

Authors and Affiliations

  • Rajesh Kumar
    • 1
  • Angela Huebner
    • 2
  • Gordon W. Laurie
    • 1
  1. 1.Department of Cell BiologyUniversity of VirginiaCharlottesvilleUSA
  2. 2.Children’s HospitalTechnical University DresdenDresdenGermany

Personalised recommendations