Cleft lip and cleft palate is a highly common congenital deformity occurring in about 1 in 700 live births. This congenital deformity occurs early in gestation at about 5 weeks. The formation of a cleft lip and cleft palate is the result of a failure of the medial nasal and maxillary processes to merge during facial morphogenesis. Cleft abnormalities result in problems with speech, the ability to eat as well as a higher susceptibility to ear infections.
IRF6 Gene
In the August 19, 2004, issue of the "New England Journal of Medicine," an international team of researchers studied families from ten populations to understand the role of genetic mutations in cleft deformities. The study identified a variant in the gene encoding interferon regulatory factor 6 (IRF6) as a major contributor to cleft lip and cleft palate in Van der Woude's syndrome. Van der Woude's syndrome is an autosomal dominant cleft deformity caused by the substitution of isoleucine for valine at amino acid position 274. This substitution interferes with the gene function resulting in cleft abnormality as well as tripling the risk of the cleft abnormalities in affected families. (Reference 1)
MSX1 Gene
MSX1 is a regulatory gene, providing instructions for the production of proteins that regulate the activity of other genes. Furthermore, the MSX1 gene is mandatory for the normal development of teeth and other oral structures. A loss of the MSX1 gene disrupts the formation of normal oral structures early in development, leading to dental abnormalities, as well as a cleft palate and cleft lip in individuals with Wolf-Hirschhorn syndrome, notes Genetics Home Reference. (Reference 2) According to the March 23, 2003, issue of "Journal of Medical Genetics", Jeweski and his associates conducted a population scan of mutations in the MSX1 gene in 917 individuals. The study showed that two percent of patients with cleft palate or cleft lip had missense mutations in coding regions or highly conserved regulatory elements of the MSX1 gene. (Reference 3)
PHF8 Gene
According to the National Center for Biotechnology Information, mutations in the PHF8 gene are linked to mental retardation, cleft lip and cleft palate as well as facial deformities. A PHF8 missense mutation, c.836C>T, modifies a conserved hydrophobic region thereby making the gene catalytically inactive. Furthermore, the activity of PHF8 gene is dependent on oxygen availability, and it has been shown that occurrences cleft lip and cleft palate is linked indirectly to low levels of maternal oxygen. (Reference 4)
References
- "New England Journal of Medicine"; Interferon Regulatory Factor 6 (IRF6) Gene Variants and the Risk of Isolated Cleft Lip or Palate; Theresa M. Zucchero et al; August 2004
- Genetics Home Reference: MSX1
- "Journal of Medical Genetics"; Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate; Jeweski P. A et al; March 2003
- Pubmed.gov: PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase.
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