LCT – Congenital Lactase Deficiency

Congenital lactase deficiency (CLD) is a severe autosomal recessive disorder presenting within days of birth with osmotic watery diarrhea, failure to thrive, malnutrition, metabolic acidosis, nephrocalcinosis, hypertonic dehydration, and weight loss. CLD arises from biallelic loss-of-function variants in LCT, encoding lactase-phlorizin hydrolase (LPH), necessary for lactose digestion. Early genetic diagnosis avoids invasive intestinal biopsy and enables timely dietary intervention.

Initial genetic linkage in 19 Finnish families mapped CLD to chromosome 2q21, where sequencing revealed five distinct LCT coding mutations, including the Finnish founder nonsense mutation c.4170T>A (p.Tyr1390Ter) in 27/32 probands and four rare LoF and missense alleles (e.g., c.804G>T (p.Gln268His)) ([PMID:16400612]). Subsequent case reports identified compound heterozygous truncating mutations c.4419C>G (p.Tyr1473Ter) and c.5387delA (p.Asp1796AlafsTer18) in a Japanese infant ([PMID:22688420], [PMID:25881162]) and homozygosity for c.3448delT (p.Ser1150ProfsTer19) in a Central European neonate ([PMID:26215149]). Additional series uncovered further private alleles across diverse populations.

The inheritance is autosomal recessive, with no affected heterozygous carriers reported. Across studies, at least 44 probands harbor biallelic LCT variants comprising nonsense, frameshift, splice-site, and missense changes, with no evidence of dominant-negative mechanisms. A representative variant is c.4419C>G (p.Tyr1473Ter).

Functional assays in COS-1 and COS-7 cells demonstrate that truncating and missense mutants (e.g., p.Tyr1390Ter, p.Gly1363Ser, p.Tyr1473Ter, p.Asp1796AlafsTer18) are misfolded, retained in the endoplasmic reticulum, subject to degradation, and lack detectable lactase activity ([PMID:25881162], [PMID:19208354], [PMID:35007711]). Hypomorphic variants likewise fail to traffic or hydrolyze lactose, confirming loss-of-function as the pathogenic mechanism.

No studies have refuted the association. The abundant genetic and concordant functional data firmly establish LCT as the definitive gene for CLD. High-throughput carrier screening and prenatal diagnosis are now feasible.

Key Take-home: Biallelic LCT loss-of-function variants cause congenital lactase deficiency via ER retention and loss of enzymatic activity, enabling prompt genetic diagnosis and management.

References

• American journal of human genetics • 2006 • Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. PMID:16400612
• The Tohoku journal of experimental medicine • 2012 • Two novel mutations in the lactase gene in a Japanese infant with congenital lactase deficiency. PMID:22688420
• BMC gastroenterology • 2015 • A novel mutation within the lactase gene (LCT): the first report of congenital lactase deficiency diagnosed in Central Europe. PMID:26215149
• BMC gastroenterology • 2015 • Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene. PMID:25881162
• Gastroenterology • 2009 • Impaired trafficking and subcellular localization of a mutant lactase associated with congenital lactase deficiency. PMID:19208354
• Biochimica et biophysica acta. Molecular basis of disease • 2022 • Hypomorphic variants of lactase-phlorizin hydrolase in congenital lactase deficiency are trafficking incompetent and functionally inactive. PMID:35007711

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