A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD

Article metrics

Abstract

We report here the identification of a new human homeobox gene, PITX3, and its involvement in anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts in humans. The PITX3 gene is the human homologue of the mouse Pitx3 gene and is a member of the RIEG/PITX homeobox gene family. The protein encoded by PITX3 shows 99% amino-acid identity to the mouse protein, with 100% identity in the homeodomain and approximately 70% overall identity to other members of this family. We mapped the human PITX3 gene to 10q25 using a radiation-hybrid panel. A collection of 80 DNA samples from individuals with various eye anomalies was screened for mutations in the PITX3 gene. We identified two mutations in independent patients. A 17-bp insertion in the 3´-end of the coding sequence, resulting in a frame shift, occured in a patient with ASMD and cataracts, and a G→A substitution, changing a codon for serine into a codon for asparagine, in the 5´-end of the gene occured in a patient with congenital cataracts. Both mutations cosegregate with the disease phenotype in families, and neither were found in up to 300 control individuals studied. Further expression analysis of Pitx3in the mouse supports a unique role in early ocular development, with later expression extending to the midbrain, tongue, incisors, sternum, vertebrae and limbs. These data strongly suggest a role for PITX3 in ASMD and cataracts and provide new evidence of the contribution of the RIEG/PITX gene family to the developmental program underpinning normal eye formation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Amino-acid sequence of the PITX3 protein (deduced from nucleotide sequence).
Figure 2: In situ hybridization with a Pitx3 riboprobe on section at the eye level of day-16-pc embryo.
Figure 3: In situ hybridization with a Pitx3 riboprobe of mouse embryo sections.
Figure 4: Variable expressivity in anterior segment mesenchymal dysgenesis family.
Figure 5: A mutation in PITX3 in the ASMD family.
Figure 6: A mutation in PITX3 in the family with dominant cataract (ADCC).

References

  1. 1

    Sarfarazi, M. Recent advances in molecular genetics of glaucomas. Hum. Mol. Genet. 6, 16667–16677 (1997).

  2. 2

    Marner, E. Rosenburg, T. Eiberg, H. Autosomal dominant congenital cataract: morphology and genetic mapping. Acta Opthalmologica 67, 151–158 (1989).

  3. 3

    Brakendorf, R.H. Henskens, H.A. van Rossum, M.W. Lubsen, N.H. Schoenmakers, J.G. Activation of the gemma E-crystallin pseudogene in the human hereditary Coppock-like cataract. Hum. Mol. Genet. 3, 279–283 ( 1994).

  4. 4

    Litt, M. et al. Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human beta-Crystallin gene CRYBB2. Hum. Mol. Genet . 6, 665–668 ( 1997).

  5. 5

    Glaser, T. et al. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nature Genet. 7, 463–471 ( 1994).

  6. 6

    Quiring, R. Walldorf, U. Kloter, U. Gehring, W.J. Homology of the eyeless gene of Drosophila to the Small eye gene in mice and Aniridia in humans. Science 5, 785–789 ( 1994).

  7. 7

    Kumar, J. Moses, K. Transcription factors in eye development: a gorgeous mosaic? Genes Dev. 11, 2023–2028 (1997).

  8. 8

    Semina, E.V. et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genet . 14, 392–399 ( 1996).

  9. 9

    Semina, E.V. Reiter, R.S. Murray, J. Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum. Mol. Genet. 6, 2109–2116 (1997).

  10. 10

    Lamonerie, T. et al. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev. 10, 1284–1295 (1996).

  11. 11

    Szeto, D.P. Ryan, A.K. O'Connell, S.M. Rosenfeld, M.G. P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc. Natl. Acad. Sci. USA 93, 7706–7710 (1996).

  12. 12

    Smidt, M.P. et al. A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc. Natl. Acad. Sci. USA 94 , 13305–13310 (1997).

  13. 13

    Hittner, H.M. Kretzer, F.L. Antoszyk, J.H. Ferrell, R.E. Mehta, R.S. Variable expressivity of autosomal dominant anterior segment mesenchymal dysgenesis in six generations. Am. J. Ophthalmol. 93, 57–70 (1982).

  14. 14

    Ferrell, R.E. Hittner, H.M. Kretzer, F.L. Antoszyk, J.H. Anterior segment mesenchymal dysgenesis: probable linkage to the MNS blood group on chromosome 4. Am. J. Hum. Genet. 34, 245–249 (1982).

  15. 15

    Heathcote, J.G. Sholdice, J. Walton, J.C. Willis, N.R. Sergovich, F.R. Anterior segment mesenchymal dysgenesis associated with partial duplication of the short arm of chromosome 2. Can. J. Ophthalmol. 26, 35–43 (1991).

  16. 16

    McLean, W.H. et al. Mutations in the rod 1A domain of keratins 1 and 10 in bullous congenital ichthyosiform erythroderma (BCIE). J. Invest. Dermatol. 102, 24–30 (1994).

  17. 17

    Roessler, B.J. et al. Human X-linked phosphoribosylpyrophosphate synthetase superactivity is associated with distinct point mutations in the PRPS1 gene. J. Biol. Chem. 268, 26476–26481 ( 1993).

  18. 18

    Prasad, K.S. Brandt, S.J. Target-dependent effect of phosphorylation on the DNA binding activity of the TAL1/SCL oncoprotein. J. Biol. Chem. 272, 11457–11462 ( 1997).

  19. 19

    Muslin, A.J. Tanner, J.W. Allen, P.M. Shaw, A.S. Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84, 889–897.

  20. 20

    Jaffe, L. Ryoo, H.D. Mann, R.S. A role for phosphorylation by casein kinase II in modulating Antennapedia activity in Drosophila. Genes Dev. 11, 1327–1340 (1997).

  21. 21

    Treisman, J. Harris, E. Wilson, D. Desplan, C. The homeodomain: a new face for the helix-turn-helix? Bioessays 14, 145–150 (1992).

  22. 22

    Martha, A. Strong, L.C. Ferrell, R.E. Saunders, G.F. Three novel aniridia mutations in the human PAX6 gene. Hum. Mutat. 6, 44 –49 (1995).

  23. 23

    Hanson, I.M. et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peter's anomaly. Nature Genet. 6, 168–173 (1994).

Download references

Acknowledgements

We thank the many patients who contributed samples for analysis in this study. B. Ludwig provided outstanding technical assistance. This work was supported by the CARC grant no. DE09170 and grant no. EY08893 (K. Zadnik, Principal Investigator) from the U.S. National Institutes of Health.

Author information

Correspondence to Jeffrey C. Murray.

Rights and permissions

Reprints and Permissions

About this article

Further reading