ASSIGNMENT OF THE LOCUS FOR CONGENITAL LACTASE DEFICIENCY TO 2Q21, INTHE VICINITY OF BUT SEPARATE FROM THE LACTASE-PHLORHIZIN HYDROLASE GENE

Congenital lactase deficiency (CLD) is an autosomal recessive, gastroi ntestinal disorder characterized by watery diarrhea starting during th e first 1-10 d of life, in infants fed lactose-containing milks. Since 1966, 42 patients have been diagnosed in Finland. CLD is the most sev ere form of lactase deficiency, with an almost total lack of lactase-p hlorizin hydrolase (LPH) activity on jejunal biopsy. In adult-type hyp olactasia, the most common genetic enzyme deficiency in humans, this e nzyme activity is reduced to 5%-10%. Although the activity of intestin al LPH has been found to be greatly reduced in both forms, the molecul ar pathogenesis of lactase deficiencies is unknown. On the basis of th e initial candidate-gene approach, we assigned the CLD locus to an 8-c M interval on chromosome 2q21 in 19 Finnish families. At the closest m arker locus, a specific allele 2 was present in 92% of disease alleles . On the basis of a genealogical study, the CLD mutation was found to be enriched in sparsely populated eastern and northern Finland, becaus e of a founder effect. The results of both the genealogical study and the haplotype analysis indicate that one major mutation in a novel gen e causes CLD in the Finnish population. Consequently, the critical reg ion could be restricted further, to an similar to 350-kb interval, by ancient-haplotype and linkage-disequilibrium analyses. Surprisingly, t he LPH gene was shown to lie outside the critical CLD region, excludin g it as a causative gene for CLD. The LPH locus was found to reside >2 Mb from the critical CLD region.