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Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate
  1. P A Jezewski1,
  2. A R Vieira2,9,
  3. C Nishimura2,
  4. B Ludwig2,
  5. M Johnson2,
  6. S E O’Brien2,
  7. S Daack-Hirsch2,
  8. R E Schultz2,
  9. A Weber2,
  10. B Nepomucena3,
  11. P A Romitti4,
  12. K Christensen5,
  13. I M Orioli6,
  14. E E Castilla7,
  15. J Machida8,
  16. N Natsume8,
  17. J C Murray2,4,5
  1. 1Departments of Periodontics and Oral Biology, College of Dentistry, University of Iowa, Iowa City, IA, USA
  2. 2Department of Pediatrics, University of Iowa, Iowa City, IA, USA
  3. 3HOPE Foundation, Bacolod City 6100, Philippines
  4. 4Department of Epidemiology, University of Iowa, Iowa City, IA, USA
  5. 5Centre for the Prevention of Congenital Malformations, University of Southern Denmark, DK-5000 Odense C, Denmark
  6. 6Latin American Collaborative Study of Congenital Malformations (ECLAMC) at Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
  7. 7Latin American Collaborative Study of Congenital Malformations (ECLAMC) at Department of Genetics, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil and CEMIC, Buenos Aires, Argentina
  8. 8Second Department of Oral and Maxillofacial Surgery, Aichi-Gakuin University, Nagoya 464, Japan
  9. 9Bolsista da Capes, Brasilia, Brazil
  1. Correspondence to:
 Dr J C Murray, Department of Pediatrics, University of Iowa, 2182 ML Iowa City, IA 52242, USA;


MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.

  • MSX1
  • birth defects
  • cleft lip and palate
  • homeobox

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