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. 1996 Aug;33(8):655–660. doi: 10.1136/jmg.33.8.655

PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida.

F A Hol 1, M P Geurds 1, S Chatkupt 1, Y Y Shugart 1, R Balling 1, C T Schrander-Stumpel 1, W G Johnson 1, B C Hamel 1, E C Mariman 1
PMCID: PMC1050699  PMID: 8863157

Abstract

From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD.

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Selected References

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  1. Ardinger H. H., Buetow K. H., Bell G. I., Bardach J., VanDemark D. R., Murray J. C. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet. 1989 Sep;45(3):348–353. [PMC free article] [PubMed] [Google Scholar]
  2. Aymé S., Philip N. Possible homozygous Waardenburg syndrome in a fetus with exencephaly. Am J Med Genet. 1995 Nov 6;59(2):263–265. doi: 10.1002/ajmg.1320590227. [DOI] [PubMed] [Google Scholar]
  3. Baldwin C. T., Hoth C. F., Amos J. A., da-Silva E. O., Milunsky A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature. 1992 Feb 13;355(6361):637–638. doi: 10.1038/355637a0. [DOI] [PubMed] [Google Scholar]
  4. Balling R., Deutsch U., Gruss P. undulated, a mutation affecting the development of the mouse skeleton, has a point mutation in the paired box of Pax 1. Cell. 1988 Nov 4;55(3):531–535. doi: 10.1016/0092-8674(88)90039-6. [DOI] [PubMed] [Google Scholar]
  5. Begleiter M. L., Harris D. J. Waardenburg syndrome and meningocele. Am J Med Genet. 1992 Nov 1;44(4):541–541. doi: 10.1002/ajmg.1320440434. [DOI] [PubMed] [Google Scholar]
  6. Burri M., Tromvoukis Y., Bopp D., Frigerio G., Noll M. Conservation of the paired domain in metazoans and its structure in three isolated human genes. EMBO J. 1989 Apr;8(4):1183–1190. doi: 10.1002/j.1460-2075.1989.tb03490.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carezani-Gavin M., Clarren S. K., Steege T. Waardenburg syndrome associated with meningomyelocele. Am J Med Genet. 1992 Jan 1;42(1):135–136. doi: 10.1002/ajmg.1320420127. [DOI] [PubMed] [Google Scholar]
  8. Chatkupt S., Chatkupt S., Johnson W. G. Waardenburg syndrome and myelomeningocele in a family. J Med Genet. 1993 Jan;30(1):83–84. doi: 10.1136/jmg.30.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chatkupt S., Hol F. A., Shugart Y. Y., Geurds M. P., Stenroos E. S., Koenigsberger M. R., Hamel B. C., Johnson W. G., Mariman E. C. Absence of linkage between familial neural tube defects and PAX3 gene. J Med Genet. 1995 Mar;32(3):200–204. doi: 10.1136/jmg.32.3.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chenevix-Trench G., Jones K., Green A. C., Duffy D. L., Martin N. G. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Am J Hum Genet. 1992 Dec;51(6):1377–1385. [PMC free article] [PubMed] [Google Scholar]
  11. Estibeiro J. P., Brook F. A., Copp A. J. Interaction between splotch (Sp) and curly tail (ct) mouse mutants in the embryonic development of neural tube defects. Development. 1993 Sep;119(1):113–121. doi: 10.1242/dev.119.1.113. [DOI] [PubMed] [Google Scholar]
  12. Helwig U., Imai K., Schmahl W., Thomas B. E., Varnum D. S., Nadeau J. H., Balling R. Interaction between undulated and Patch leads to an extreme form of spina bifida in double-mutant mice. Nat Genet. 1995 Sep;11(1):60–63. doi: 10.1038/ng0995-60. [DOI] [PubMed] [Google Scholar]
  13. Hol F. A., Geurds M. P., Jensson O., Hamel B. C., Moore G. E., Newton R., Mariman E. C. Exclusion mapping of the gene for X-linked neural tube defects in an Icelandic family. Hum Genet. 1994 Apr;93(4):452–456. doi: 10.1007/BF00201674. [DOI] [PubMed] [Google Scholar]
  14. Hol F. A., Hamel B. C., Geurds M. P., Mullaart R. A., Barr F. G., Macina R. A., Mariman E. C. A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome. J Med Genet. 1995 Jan;32(1):52–56. doi: 10.1136/jmg.32.1.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hoth C. F., Milunsky A., Lipsky N., Sheffer R., Clarren S. K., Baldwin C. T. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet. 1993 Mar;52(3):455–462. [PMC free article] [PubMed] [Google Scholar]
  16. Macina R. A., Barr F. G., Galili N., Riethman H. C. Genomic organization of the human PAX3 gene: DNA sequence analysis of the region disrupted in alveolar rhabdomyosarcoma. Genomics. 1995 Mar 1;26(1):1–8. doi: 10.1016/0888-7543(95)80076-x. [DOI] [PubMed] [Google Scholar]
  17. Mariman E. C., Hamel B. C. Sex ratios of affected and transmitting members of multiple case families with neural tube defects. J Med Genet. 1992 Oct;29(10):695–698. doi: 10.1136/jmg.29.10.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moase C. E., Trasler D. G. Splotch locus mouse mutants: models for neural tube defects and Waardenburg syndrome type I in humans. J Med Genet. 1992 Mar;29(3):145–151. doi: 10.1136/jmg.29.3.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moline M. L., Sandlin C. Waardenburg syndrome and meningomyelocele. Am J Med Genet. 1993 Aug 1;47(1):126–126. doi: 10.1002/ajmg.1320470130. [DOI] [PubMed] [Google Scholar]
  21. Narod S. A., Siegel-Bartelt J., Hoffman H. J. Cerebellar infarction in a patient with Waardenburg syndrome. Am J Med Genet. 1988 Dec;31(4):903–907. doi: 10.1002/ajmg.1320310424. [DOI] [PubMed] [Google Scholar]
  22. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991 Jul 20;338(8760):131–137. [PubMed] [Google Scholar]
  23. Stapleton P., Weith A., Urbánek P., Kozmik Z., Busslinger M. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nat Genet. 1993 Apr;3(4):292–298. doi: 10.1038/ng0493-292. [DOI] [PubMed] [Google Scholar]
  24. Strachan T., Read A. P. PAX genes. Curr Opin Genet Dev. 1994 Jun;4(3):427–438. doi: 10.1016/0959-437x(94)90032-9. [DOI] [PubMed] [Google Scholar]
  25. Tassabehji M., Newton V. E., Leverton K., Turnbull K., Seemanova E., Kunze J., Sperling K., Strachan T., Read A. P. PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the Splotch mouse. Hum Mol Genet. 1994 Jul;3(7):1069–1074. doi: 10.1093/hmg/3.7.1069. [DOI] [PubMed] [Google Scholar]
  26. Tassabehji M., Read A. P., Newton V. E., Harris R., Balling R., Gruss P., Strachan T. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature. 1992 Feb 13;355(6361):635–636. doi: 10.1038/355635a0. [DOI] [PubMed] [Google Scholar]
  27. Wallin J., Wilting J., Koseki H., Fritsch R., Christ B., Balling R. The role of Pax-1 in axial skeleton development. Development. 1994 May;120(5):1109–1121. doi: 10.1242/dev.120.5.1109. [DOI] [PubMed] [Google Scholar]
  28. Wilcox E. R., Rivolta M. N., Ploplis B., Potterf S. B., Fex J. The PAX3 gene is mapped to human chromosome 2 together with a highly informative CA dinucleotide repeat. Hum Mol Genet. 1992 Jun;1(3):215–215. doi: 10.1093/hmg/1.3.215-a. [DOI] [PubMed] [Google Scholar]
  29. de Saxe M., Kromberg J. G., Jenkins T. Waardenburg syndrome in South Africa. Part I. An evaluation of the clinical findings in 11 families. S Afr Med J. 1984 Aug 18;66(7):256–261. [PubMed] [Google Scholar]

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