Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD)

Abstract

BackgroundCongenital lactase deficiency (CLD) is a severe gastrointestinal disorder of newborns. The diagnosis is challenging and based on clinical symptoms and low lactase activity in intestinal biopsy specimens. The disease is enriched in Finland but is also present in other parts of the world. Mutations encoding the lactase (LCT) gene have recently been shown to underlie CLD. The purpose of this study was to identify new mutations underlying CLD in patients with different ethnic origins, and to increase awareness of this disease so that the patients could be sought out and treated correctly.MethodsDisaccharidase activities in intestinal biopsy specimens were assayed and the coding region of LCT was sequenced from five patients from Europe with clinical features compatible with CLD. In the analysis and prediction of mutations the following programs: ClustalW, Blosum62, PolyPhen, SIFT and Panther PSEC were used.ResultsFour novel mutations in the LCT gene were identified. A single nucleotide substitution leading to an amino acid change S688P in exon 7 and E1612X in exon 12 were present in a patient of Italian origin. Five base deletion V565fsX567 leading to a stop codon in exon 6 was found in one and a substitution R1587H in exon 12 from another Finnish patient. Both Finnish patients were heterozygous for the Finnish founder mutation Y1390X. The previously reported mutation G1363S was found in a homozygous state in two siblings of Turkish origin.ConclusionThis is the first report of CLD mutations in patients living outside Finland. It seems that disease is more common than previously thought. All mutations in the LCT gene lead to a similar phenotype despite the location and/or type of mutation.

Two Novel Mutations in the Lactase Gene in a Japanese Infant with Congenital Lactase Deficiency

“…The incidence of CLD was estimated to be 1:60 000 newborns in Finland on the basis of the number of patients who had been diagnosed until 1998 (Järvelä et al 1998). After the molecular background of CLD was confirmed, the number of patients newly diagnosed with CLD in Finland increased, and the novel LCT mutations were reported in the CLD patients with different ethnic origins (Torniainen et al 2009). In Japan, only few cases of CLD have been reported since Akabane and Arakawa published the first case in 1965 (Akabane 1965;Yabuuchi et al 1966;Nose et al 1979).…”

“…Domain IV comprises lactase activity, and domains I-III act as intramolecular chaperone which is critical for the maturation during lactase-folding process (Kuokkanen et al 2006;Behrendt et al 2009). To date, nine mutations are known to underlie CLD and there are quite evenly distributed covering both the pro-region and the mature lactase (Kuokkanen et al 2006;Torniainen et al 2009). Five of them result in a premature stop codon.…”

Lactose Intolerance: Common Misunderstandings

“…The typical feature of CLD is the absence or very low levels of lactase expression deriving from a mutation in lactase phlorizin hydrolase gene (LPH) located on 2q21.3 [5, 6]. Most CLD cases have been described in Finland, where the disorder is enriched due to a founder effect and genetic drift [5, 7]. Premature stop codons and a truncated protein as a result of frame shifts, missense mutations in the coding region of LPH, or exon duplication are the most common genotypes identified in these patients [7-10].…”

“…Most CLD cases have been described in Finland, where the disorder is enriched due to a founder effect and genetic drift [5, 7]. Premature stop codons and a truncated protein as a result of frame shifts, missense mutations in the coding region of LPH, or exon duplication are the most common genotypes identified in these patients [7-10]. Some other cases include mutations leading to single amino acid substitutions that can interfere with the proper maturation and function of LPH [7, 11].…”

“…Premature stop codons and a truncated protein as a result of frame shifts, missense mutations in the coding region of LPH, or exon duplication are the most common genotypes identified in these patients [7-10]. Some other cases include mutations leading to single amino acid substitutions that can interfere with the proper maturation and function of LPH [7, 11]. More recently, severe forms of CLD elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance have been described [3].…”