Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC, M IM 248250) is a complex renal tubular disorder characterised by hypomagnesa emia, hypercalciuria, advanced nephrocalcinosis, hyposthenuria and progress ive renal failure. The mode of inheritance is autosomal recessive. A primar y defect in the reabsorption of magnesium in the medullary thick ascending limb of the loop of Henle (mTAL) has been proposed to be essential in FHHNC pathophysiology. To identify the underlying genetic defect we performed li nkage analysis in eight families, including three with consanguineous marri ages. We found linkage to microsatellite markers on chromosome 3q27 with a maximum two-point lod score (Z(max)) of 5.208 for D3S3530 without evidence for genetic heterogeneity. Haplotype analysis revealed crucial recombinatio n events reducing the critical interval to 6.6 cM. Recently, mutations in t he gene PCLN-1, mapping to 3q27 and coding for paracellin-1, were identifie d by Simon et al (1999) as the underlying genetic defect in FHHNC. Paracell in-1 represents a renal tight junction protein predominantly expressed in t he TAL. Mutational analysis in our patient cohort revealed eight different mutations in the PCLN-1 gene, within six novel mutations. In seven of 13 mu tant alleles we detected a Leu151 substitution without evidence for a found er effect. Leu151 is a residue of the first extracellular loop of paracelli n-1, the part of the protein expected to bridge the intercellular space and to be important for paracellular conductance. This study confirms the impl ication of paracellin-1 defects in FHHNC and points to a predominant role o f this protein in the paracellular reabsorption of divalent cations in the TAL.