In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine. The consequent severe diarrhoea and dehydration are usually fatal unless these sugars are eliminated from the diet. Intestinal biopsies of GGM patients have revealed a specific defect in Na(+)-dependent absorption of glucose in the brush border. Normal glucose absorption is mediated by the Na+/glucose cotransporter in the brush border membrane of the intestinal epithelium. Cellular influx is driven by the transmembrane Na+ electrochemical potential gradient; thereafter the sugar moves to the blood across the basolateral membrane via the facilitated glucose carrier. We have previously cloned and sequenced a Na+/glucose cotransporter from normal human ileum and shown that this gene, SGLT1, resides on the distal q arm of chromosome 22. We have now amplified SGLT1 complementary DNA and genomic DNA from members of a family affected with GGM by the polymerase chain reaction. Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na(+)-dependent glucose transport in Xenopus oocytes injected with this complementary RNA.

Wolcott-Rallison syndrome (WRS) is

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type I procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type I procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha1(I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.

On page 555 under the section titled Mutations in FKBP10 cause Recessive OI, there are two errors in the nomenclature for the identified mutations. The FKBP10 (NM_021939.3) mutation isolated in the Turkish cases (proband R06-113A) is c.321_353 del and is predicted to result in the deletion of eleven amino acids in the protein, p.Met107_Leu117 del. In the second paragraph of the subheading, the mutation in the Mexican-American family (proband R93-188) should be