Gene Mutation
Recently, mutations in the coding region of lactase (LCT) gene were revealed to be the underlying cause of Congenital Lactase Deficiency (CLD) and the molecular background is being identified. The LCT gene consists of 17 exons encoding 1927 amino acids comprising four homologous domains, I – IV. Domain IV harbors lactase activity. One mutation, c4170T>A (p.Y1390X) in exon 9, is enriched in Finnish population, and 84% of Finnish patients were homozygous for this mutation. Y1390X is located in domain IV, and results in a truncation of lactase.
To date, nine mutations are known to underlie CLD and there are quite evenly distributed covering both the pro-region and the mature lactase. These result in a premature stop codon. One of the missense mutations, G1363S, located in the domain III, leads to defective lactase activity and impaired trafficking of mutant lactase polypeptide to the cell surface at physiological temperature. Mutations E1612X and R1587H are located in the conserved region IV of the mature LCT that encodes lactase activity (Figure 1). Mutation E1612X leads to a truncated protein. In substitution R1587H both amino acids are polar, basic amino acids. However, arginine always has a positive charge and a role in the maintenance of protein overall charge balance. Therefore, the substitution to histidine (which charge depends on environment) may disturb the overall charge. Substitution S688P and deletion V565fsX567 are located in the region II of the pro-LPH that has been shown to have a role as an intramolecular chaperone in the folding of the LPH-protein (Figure 1). Deletion V565fsX567 leads to truncated protein after a few amino acids. A change from a non-aromatic polar serine to cyclic and non-polar proline causes a remarkable change in the chemical and physical properties of the protein.
To date, nine mutations are known to underlie CLD and there are quite evenly distributed covering both the pro-region and the mature lactase. These result in a premature stop codon. One of the missense mutations, G1363S, located in the domain III, leads to defective lactase activity and impaired trafficking of mutant lactase polypeptide to the cell surface at physiological temperature. Mutations E1612X and R1587H are located in the conserved region IV of the mature LCT that encodes lactase activity (Figure 1). Mutation E1612X leads to a truncated protein. In substitution R1587H both amino acids are polar, basic amino acids. However, arginine always has a positive charge and a role in the maintenance of protein overall charge balance. Therefore, the substitution to histidine (which charge depends on environment) may disturb the overall charge. Substitution S688P and deletion V565fsX567 are located in the region II of the pro-LPH that has been shown to have a role as an intramolecular chaperone in the folding of the LPH-protein (Figure 1). Deletion V565fsX567 leads to truncated protein after a few amino acids. A change from a non-aromatic polar serine to cyclic and non-polar proline causes a remarkable change in the chemical and physical properties of the protein.
In addition, from the journal above, it reported two novel mutations in the LCT gene in a Japanese female infant with clinical features consistent with that CLD. She suffered from severe watery diarrhea from the age of 2 days on breast milk/lactose containing cow’s milk formula. Sequences analysis revealed that the two mutations in her LCT gene in a heterozygous form: c.4419C>G (p.Y1473X) in exon 10 and c.5387delA ( p.D1796fs) in exon 16. Both mutations located in the domain IV. These mutations lead to premature truncation of lactase polypeptide and are supposed to be responsible for CLD.
Source:
1. Uchida et al., "Two novel mutations in the lactase gene in a Japanese infant with congenital lactase deficiency", Tohoku, J Exp Med. 2012;227(1):69-72.
http://www.ncbi.nlm.nih.gov/pubmed/22688420
2. Torniainen S, F. R., Routi T, Gijsbers C, Catassi C, Höglund P, Savilahti E, Järvelä I (2009). 'Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD)'. http://www.ncbi.nlm.nih.gov/pubmed/19161632
Source:
1. Uchida et al., "Two novel mutations in the lactase gene in a Japanese infant with congenital lactase deficiency", Tohoku, J Exp Med. 2012;227(1):69-72.
http://www.ncbi.nlm.nih.gov/pubmed/22688420
2. Torniainen S, F. R., Routi T, Gijsbers C, Catassi C, Höglund P, Savilahti E, Järvelä I (2009). 'Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD)'. http://www.ncbi.nlm.nih.gov/pubmed/19161632