Involvement of claudin 3 and claudin 4 in idiopathic infantile hypercalcaemia: a novel hypothesis?
BACKGROUND
Idiopathic infantile hypercalcaemia (IIH) is a rare disease that generally resolves spontaneously between the age of 1 and 3 years. Similar symptoms may occur in patients suffering from Williams-Beuren syndrome (WBS), which is caused by a microdeletion on chromosome 7. Two of the genes, named CLDN3 and CLDN4, located within this region are members of the claudin family that has been shown to be involved in paracellular calcium (Ca(2+)) absorption. Based on the hemizygous loss of CLDN3 and CLDN4 in WBS and the function of these genes in paracellular Ca(2+) transport, we hypothesized that mutations in CLDN3 or CLDN4 could also be involved in IIH.


METHODS
Biochemical characteristics, including calciotropic hormone levels, were obtained from three typical IIH patients. CLDN3 and CLDN4 sequences were also analysed in these patients. The major intestinal Ca(2+) transporter TRPV6 was also screened for the presence of mutations, since hypercalcaemia in IIH and WBS has been shown to result from intestinal hyperabsorption. All three patients were also analysed for the presence of deletions or duplications using a single-nucleotide polymorphism (SNP) array for genomic DNA.


RESULTS
The serum Ca(2+) levels of patients were 2.9, 3.3 and 3.8 mmol/L (normal <2.7 mmol/L). Levels of 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) were normal, parathyroid hormone (PTH) and PTH-related peptide (PTHrP) levels were appropriately low. Sequencing of coding regions and intron-exon boundaries did not reveal mutations in CLDN3, CLDN4 and TRPV6. Identified SNPs were not correlated with the disease phenotype. A SNP array did not reveal genomic deletions or duplications.


CONCLUSIONS
Biochemical analysis did not reveal inappropriate levels of calciotropic hormones in IIH patients in this study. Furthermore, based on the lack of mutations in CLDN3, CLDN4 and TRPV6, we conclude that IIH is neither caused by mutations in these candidate genes nor by deletions or duplications in the genome of these patients.
Lameris
Anke L L
AL
Department of Physiology, Radboud University Nijmegen Medical Centre, The Netherlands.
Huybers
Sylvie
S
Burke
John R
JR
Monnens
Leo A
LA
Bindels
René J M
RJ
Hoenderop
Joost G J
JG
D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D015220:Calcium Channels / Q000235:genetics; D062465:Claudin-3; D062506:Claudin-4; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology*; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D010281:Parathyroid Hormone / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D050916:TRPV Cation Channels / Q000235:genetics
C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D015220:Calcium Channels; D062465:Claudin-3; D062506:Claudin-4; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human; D002117:Calcitriol; D002118:Calcium