Congenital Lactase Deficiency: Mutations, Functional and Biochemical Implications, and Future Perspectives

Area of Science:

• Genetics
• Biochemistry
• Pediatrics

Background:

• Congenital lactase deficiency (CLD) is a rare, severe autosomal recessive disorder impacting intestinal lactase-phlorizin hydrolase (LPH) function.
• It manifests in newborns with severe osmotic watery diarrhea due to an inability to digest lactose, the primary carbohydrate in milk.
• CLD symptoms resemble other congenital carbohydrate malabsorption disorders.

Purpose of the Study:

• To review current knowledge of mutations associated with congenital lactase deficiency (CLD).
• To analyze the potential impact of these mutations on the structural and biosynthetic properties of lactase-phlorizin hydrolase (LPH).
• To discuss potential pathomechanisms, carrier symptomatology, and the necessity of genetic testing for CLD.

Main Methods:

• Literature review of congenital lactase deficiency (CLD) and LPH gene mutations.
• Analysis of genotype-phenotype correlations and their implications for LPH protein structure and function.
• Discussion of inheritance patterns, mutation types, and potential disease mechanisms.

Main Results:

• CLD is caused by loss-of-function mutations in the LPH gene, occurring in homozygous or compound heterozygous patterns.
• Mutations include missense variants and those causing truncations in critical LPH domains, affecting folding, transport, and catalytic activity.
• Detailed genotype/protein phenotype analyses are lacking, hindering a full understanding of CLD pathomechanisms.

Conclusions:

• Understanding CLD mutations is crucial for elucidating LPH dysfunction and disease pathogenesis.
• Further research into genotype-phenotype relationships is needed to fully characterize CLD.
• The review addresses the clinical significance of heterozygote carriers and the role of genetic testing in managing this severe disorder.