Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency.
Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. We initially assigned the CLD locus by linkage and linkage disequilibrium on 2q21 in 19 Finnish families. Here we report the molecular background of CLD via characterization of five distinct mutations in the coding region of the lactase (LCT) gene. Twenty-seven patients out of 32 (84%) were homozygous for a nonsense mutation, c.4170T-->A (Y1390X), designated "Fin(major)." Four rare mutations--two that result in a predicted frameshift and early truncation at S1666fsX1722 and S218fsX224 and two point mutations that result in substitutions Q268H and G1363S of the 1,927-aa polypeptide--confirmed the lactase mutations as causative for CLD. These findings facilitate genetic testing in clinical practice and enable genetic counseling for this severe disease. Further, our data demonstrate that, in contrast to common adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy form represents the outcome of mutations affecting the structure of the protein inactivating the enzyme.
Kuokkanen
Mikko
M
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
Kokkonen
Jorma
J
Enattah
Nabil Sabri
NS
Ylisaukko-Oja
Tero
T
Komu
Hanna
H
Varilo
Teppo
T
Peltonen
Leena
L
Savilahti
Erkki
E
Jarvela
Irma
I
D004252:DNA Mutational Analysis; D005260:Female; D005817:Genetic Counseling; D006720:Homozygote; D006801:Humans; D043322:Lactase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D007787:Lactose Intolerance / Q000235:genetics*; D008297:Male; D009154:Mutation; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D043322:Lactase