Assignment of the Locus for Congenital Lactase Deficiency to 2q21, in the Vicinity of but Separate from the Lactase-Phlorizin Hydrolase Gene

Abstract

Congenital lactase deficiency (CLD) is an autosomal recessive, gastrointestinal disorder characterized by watery diarrhea starting during the 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 severe form of lactase deficiency, with an almost total lack of lactase-phlorizin hydrolase (LPH) activity on jejunal biopsy. In adult-type hypolactasia, the most common genetic enzyme deficiency in humans, this enzyme activity is reduced to 5%-10%. Although the activity of intestinal LPH has been found to be greatly reduced in both forms, the molecular pathogenesis of lactase deficiencies is unknown. On the basis of the initial candidate-gene approach, we assigned the CLD locus to an 8-cM interval on chromosome 2q21 in 19 Finnish families. At the closest marker 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, because of a founder effect. The results of both the genealogical study and the haplotype analysis indicate that one major mutation in a novel gene causes CLD in the Finnish population. Consequently, the critical region could be restricted further, to an approximately 350-kb interval, by ancient-haplotype and linkage-disequilibrium analyses. Surprisingly, the LPH gene was shown to lie outside the critical CLD region, excluding it as a causative gene for CLD. The LPH locus was found to reside >2 Mb from the critical CLD region.

Prevalence of adult-type hypolactasia as diagnosed with genetic and lactose hydrogen breath tests in Hungarians

“…The positive HBT results conflicting with the genotypes may be a consequence of accelerated intestinal transit, secondary lactose malabsorption because of inflammation, coeliac disease, giardiasis, bacterial or viral infections, a carrier status of a congenital lactase deficiency (Järvelä et al, 1998) or other genetic factors (Enattah et al, 2008). Nevertheless, we were not able to detect any other SNP responsible for the ATH-related symptoms in the close vicinity of the C/T À13910 variant.…”

The Causal Element for the Lactase Persistence/ non‐persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

“…This sequence was used to generate single-copy PCR products, to rescreen the libraries, and chromosome walking was continued using this approach. Mapping the ends of D2S442 positive clones on to previously mapped YACs ( Jarvela et al 1998) oriented them with respect to LCT, and further orientations were deduced by the patterns of positive and negative signal obtained by PCR amplification of single copy sequence using other clones as templates. BAC clones from the RPCI-11 library, arranged in contigs and sequenced to first draft standard at the Genome Sequencing Center at the University of Washington Medical School at St Louis, were used to extend the map and particularly to identify SNPs on the other side of LCT.…”

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

“…A few cases of CLD in patients with different ethnic origins have also been reported. The incidence of CLD was estimated to be 1:60 000 newborns in Finland on the basis of the number of patients who had been diagnosed until 1998 (Järvelä et al 1998). After the molecular background of CLD was confirmed, the number of patients newly diagnosed with CLD in Finland increased, and the novel LCT mutations were reported in the CLD patients with different ethnic origins (Torniainen et al 2009).…”