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J Med Genet. Jun 2003; 40(6): 399–407.
PMCID: PMC1735501

Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate

Abstract

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.

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Selected References

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  • Vanderas AP. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J. 1987 Jul;24(3):216–225. [PubMed]
  • FRASER FC. Thoughts on the etiology of clefts of the palate and lip. Acta Genet Stat Med. 1955;5(4):358–369. [PubMed]
  • Wyszynski DF, Beaty TH, Maestri NE. Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J. 1996 Sep;33(5):406–417. [PubMed]
  • Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet. 1999;8(10):1853–1859. [PubMed]
  • Murray JC. Gene/environment causes of cleft lip and/or palate. Clin Genet. 2002 Apr;61(4):248–256. [PubMed]
  • Ardinger HH, Buetow KH, Bell GI, Bardach J, VanDemark DR, Murray JC. 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]
  • Satokata I, Maas R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet. 1994 Apr;6(4):348–356. [PubMed]
  • Maestri NE, Beaty TH, Hetmanski J, Smith EA, McIntosh I, Wyszynski DF, Liang KY, Duffy DL, VanderKolk C. Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models. Am J Med Genet. 1997 Dec 19;73(3):337–344. [PubMed]
  • Lidral AC, Romitti PA, Basart AM, Doetschman T, Leysens NJ, Daack-Hirsch S, Semina EV, Johnson LR, Machida J, Burds A, et al. Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. Am J Hum Genet. 1998 Aug;63(2):557–568. [PMC free article] [PubMed]
  • Romitti PA, Lidral AC, Munger RG, Daack-Hirsch S, Burns TL, Murray JC. Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts. Teratology. 1999 Jan;59(1):39–50. [PubMed]
  • Blanco R, Chakraborty R, Barton SA, Carreño H, Paredes M, Jara L, Palomino H, Schull WJ. Evidence of a sex-dependent association between the MSX1 locus and nonsyndromic cleft lip with or without cleft palate in the Chilean population. Hum Biol. 2001 Feb;73(1):81–89. [PubMed]
  • Beaty TH, Wang H, Hetmanski JB, Fan YT, Zeiger JS, Liang KY, Chiu YF, Vanderkolk CA, Seifert KC, Wulfsberg EA, et al. A case-control study of nonsyndromic oral clefts in Maryland. Ann Epidemiol. 2001 Aug;11(6):434–442. [PubMed]
  • Sinsheimer Janet S, Palmer Christina G S, Woodward J Arthur. Detecting genotype combinations that increase risk for disease: maternal-fetal genotype incompatibility test. Genet Epidemiol. 2003 Jan;24(1):1–13. [PubMed]
  • van den Boogaard MJ, Dorland M, Beemer FA, van Amstel HK. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet. 2000 Apr;24(4):342–343. [PubMed]
  • Poe D. Operation Smile International: missions of mercy. Plast Surg Nurs. 1994 Winter;14(4):225–230. [PubMed]
  • Natsume N, Kawai T. Experience in teaching of cleft lip and palate surgery in Asia. Int J Oral Maxillofac Surg. 1998 Dec;27(6):487–490. [PubMed]
  • Romitti PA, Munger RG, Murray JC, Daack-Hirsch S, Hanson JW, Burns TL. The effect of follow-up on limiting non-participation bias in genetic epidemiologic investigations. Eur J Epidemiol. 1998 Feb;14(2):129–138. [PubMed]
  • Lidral AC, Murray JC, Buetow KH, Basart AM, Schearer H, Shiang R, Naval A, Layda E, Magee K, Magee W. Studies of the candidate genes TGFB2, MSX1, TGFA, and TGFB3 in the etiology of cleft lip and palate in the Philippines. Cleft Palate Craniofac J. 1997 Jan;34(1):1–6. [PubMed]
  • Dausset J, Cann H, Cohen D, Lathrop M, Lalouel JM, White R. Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics. 1990 Mar;6(3):575–577. [PubMed]
  • Blin-Wakkach C, Lezot F, Ghoul-Mazgar S, Hotton D, Monteiro S, Teillaud C, Pibouin L, Orestes-Cardoso S, Papagerakis P, Macdougall M, et al. Endogenous Msx1 antisense transcript: in vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7336–7341. [PMC free article] [PubMed]
  • Raskin S, Phillips JA, 3rd, Kaplan G, McClure M, Vnencak-Jones C. Cystic fibrosis genotyping by direct PCR analysis of Guthrie blood spots. PCR Methods Appl. 1992 Nov;2(2):154–156. [PubMed]
  • Klenerman P, Hengartner H, Zinkernagel RM. A non-retroviral RNA virus persists in DNA form. Nature. 1997 Nov 20;390(6657):298–301. [PubMed]
  • Richards B, Skoletsky J, Shuber AP, Balfour R, Stern RC, Dorkin HL, Parad RB, Witt D, Klinger KW. Multiplex PCR amplification from the CFTR gene using DNA prepared from buccal brushes/swabs. Hum Mol Genet. 1993 Feb;2(2):159–163. [PubMed]
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. [PMC free article] [PubMed]
  • Parker LT, Zakeri H, Deng Q, Spurgeon S, Kwok PY, Nickerson DA. AmpliTaq DNA polymerase, FS dye-terminator sequencing: analysis of peak height patterns. Biotechniques. 1996 Oct;21(4):694–699. [PubMed]
  • Nickerson DA, Tobe VO, Taylor SL. PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 1997 Jul 15;25(14):2745–2751. [PMC free article] [PubMed]
  • Abecasis GR, Cookson WO. GOLD--graphical overview of linkage disequilibrium. Bioinformatics. 2000 Feb;16(2):182–183. [PubMed]
  • Devlin B, Risch N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics. 1995 Sep 20;29(2):311–322. [PubMed]
  • Hewitt JE, Clark LN, Ivens A, Williamson R. Structure and sequence of the human homeobox gene HOX7. Genomics. 1991 Nov;11(3):670–678. [PubMed]
  • Padanilam BJ, Stadler HS, Mills KA, McLeod LB, Solursh M, Lee B, Ramirez F, Buetow KH, Murray JC. Characterization of the human HOX 7 cDNA and identification of polymorphic markers. Hum Mol Genet. 1992 Sep;1(6):407–410. [PubMed]
  • Hollway GE, Mulley JC. Polymorphic variants within the homeobox gene MSX1: a candidate gene for developmental disorders. Clin Genet. 1998 Aug;54(2):152–154. [PubMed]
  • Gonzalez SM, Ferland LH, Robert B, Abdelhay E. Structural and functional analysis of mouse Msx1 gene promoter: sequence conservation with human MSX1 promoter points at potential regulatory elements. DNA Cell Biol. 1998 Jun;17(6):561–572. [PubMed]
  • Zhang H, Hu G, Wang H, Sciavolino P, Iler N, Shen MM, Abate-Shen C. Heterodimerization of Msx and Dlx homeoproteins results in functional antagonism. Mol Cell Biol. 1997 May;17(5):2920–2932. [PMC free article] [PubMed]
  • Bryan JT, Morasso MI. The Dlx3 protein harbors basic residues required for nuclear localization, transcriptional activity and binding to Msx1. J Cell Sci. 2000 Nov;113(Pt 22):4013–4023. [PMC free article] [PubMed]
  • Burghes AH, Vaessin HE, de La Chapelle A. Genetics. The land between Mendelian and multifactorial inheritance. Science. 2001 Sep 21;293(5538):2213–2214. [PubMed]
  • Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science. 2001 Sep 21;293(5538):2256–2259. [PubMed]
  • Cartegni Luca, Chew Shern L, Krainer Adrian R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002 Apr;3(4):285–298. [PubMed]
  • Murray JC, Daack-Hirsch S, Buetow KH, Munger R, Espina L, Paglinawan N, Villanueva E, Rary J, Magee K, Magee W. Clinical and epidemiologic studies of cleft lip and palate in the Philippines. Cleft Palate Craniofac J. 1997 Jan;34(1):7–10. [PubMed]
  • Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA. 2001 Jun 20;285(23):2981–2986. [PubMed]
  • Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with tetralogy of fallot. Circulation. 2001 Nov 20;104(21):2565–2568. [PubMed]
  • Kondo Shinji, Schutte Brian C, Richardson Rebecca J, Bjork Bryan C, Knight Alexandra S, Watanabe Yoriko, Howard Emma, de Lima Renata L L Ferreira, Daack-Hirsch Sandra, Sander Achim, et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet. 2002 Oct;32(2):285–289. [PMC free article] [PubMed]
  • Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, Newbury-Ecob R, Hennekam RC, Van Buggenhout G, van Haeringen A, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell. 1999 Oct 15;99(2):143–153. [PubMed]
  • Sözen MA, Suzuki K, Tolarova MM, Bustos T, Fernández Iglesias JE, Spritz RA. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nat Genet. 2001 Oct;29(2):141–142. [PubMed]
  • Braybrook C, Doudney K, Marçano AC, Arnason A, Bjornsson A, Patton MA, Goodfellow PJ, Moore GE, Stanier P. The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia. Nat Genet. 2001 Oct;29(2):179–183. [PubMed]
  • Vastardis H, Karimbux N, Guthua SW, Seidman JG, Seidman CE. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet. 1996 Aug;13(4):417–421. [PubMed]
  • Jumlongras D, Bei M, Stimson JM, Wang WF, DePalma SR, Seidman CE, Felbor U, Maas R, Seidman JG, Olsen BR. A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet. 2001 Jul;69(1):67–74. [PMC free article] [PubMed]
  • Murray JC. Face facts: genes, environment, and clefts. Am J Hum Genet. 1995 Aug;57(2):227–232. [PMC free article] [PubMed]
  • Odelberg SJ, Kollhoff A, Keating MT. Dedifferentiation of mammalian myotubes induced by msx1. Cell. 2000 Dec 22;103(7):1099–1109. [PubMed]
  • Hu G, Lee H, Price SM, Shen MM, Abate-Shen C. Msx homeobox genes inhibit differentiation through upregulation of cyclin D1. Development. 2001 Jun;128(12):2373–2384. [PubMed]
  • Wang KY, Juriloff DM, Diewert VM. Deficient and delayed primary palatal fusion and mesenchymal bridge formation in cleft lip-liable strains of mice. J Craniofac Genet Dev Biol. 1995 Jul-Sep;15(3):99–116. [PubMed]

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