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

Abstract

Intestinal lactase is required for the hydrolysis of lactose that is the most essential carbohydrate in milk and the primary diet source of newborn. Congenital lactase deficiency [CLD (MIM 223000)] is a severe gastrointestinal disorder and is characterized by watery diarrhea due to an extremely low or the lack of lactase activity in the intestinal wall from birth. CLD is a rare disease and occurs more frequently in Finland. Recent studies have shown that mutations in the coding region of the lactase (LCT) gene underlie CLD in patients from Finland and other European countries. Here, we report two novel mutations in the LCT gene in a Japanese female infant with clinical features consistent with those of CLD. She suffered from severe watery diarrhea from the age of 2 days on breast milk/lactose containing cow's milk formula. With the lactose-free hydrolyzed cow's milk formula, diarrhea was stopped, and she has now developed well on a lactose-free diet. She shows a lactose-intolerance pattern on the lactose challenge test. Sequence analysis revealed the two mutations in her LCT gene: c.4419C>G (p.Y1473X) in exon 10 transmitted from her mother and c.5387delA (p.D1796fs) in exon 16 transmitted from her father. Both mutations cause premature truncation of lactase polypeptide and are supposed to be responsible for CLD. To our knowledge, this is the first report on mutations in the LCT gene in Japan. We suggest that an increased awareness is required regarding CLD.

Congenital lactase deficiency: Identification of a new mutation

“…2,3 Eleven mutations have been described to date that cause CLD. 3,6 Genetic testing of the patient revealed the homozygous duplication c.2232 2253dup22 in exon 7 of the LCT gene, which had not been described before. This is a frameshift mutation that produces a premature stop codon (p.L752KfsX18), resulting in a truncated protein that precludes the correct hydrolysis of lactose.…”

Hypercalcemic Disorders in Children

“…(69) In CLD, the severely reduced or absent activity of the gut enzyme lactase, leads to an inability to breakdown dietary lactose, which results in osmotic diarrhea, dehydration, and weight loss shortly after feeding commences, and patients typically have hypercalcemia with nephrocalcinosis. CLD, an autosomal recessive disorder, (70)(71)(72)(73) is caused by a mutation of the lactase-phlorizin hydrolase gene, with a reported incidence of 1:60,000 newborns in Finland, (73) although it can occur in other populations. (70)(71)(72)(73) Hypercalcemia in CLD usually resolves within weeks after starting a lactose-free diet, whereas nephrocalcinosis may persist for years.…”

“…CLD, an autosomal recessive disorder, (70)(71)(72)(73) is caused by a mutation of the lactase-phlorizin hydrolase gene, with a reported incidence of 1:60,000 newborns in Finland, (73) although it can occur in other populations. (70)(71)(72)(73) Hypercalcemia in CLD usually resolves within weeks after starting a lactose-free diet, whereas nephrocalcinosis may persist for years. (74) The hypercalcemia in CLD may be secondary to, or exacerbated by, dehydration and a metabolic acidosis, or be by a direct action of lactose on the gut.…”

Lactose Intolerance: Common Misunderstandings

“…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].…”