¹Department of Pediatrics, Philipps University, Marburg, Germany

²Mikrosatellitenzentrum, Max-Delbrueck-Centre, Berlin, Germany

³Department of Pediatrics, University Hospital, Erlangen, Germany

⁴Department of Pediatrics, University Hospital, Münster, Germany

⁵Department of Human Genetics, University Hospital Nijmegen, The Netherlands

⁶Pediatric Nephrology Unit, Edouard-Herriot Hospital, Lyon, France

⁷Department of Pediatrics, University Hospital, Ostrava, Czech Republic

⁸Department of Pediatric Nephrology, University Children's Hospital, Essen, Germany

⁹Research Institute of Child Nutrition, Dortmund, Germany

¹⁰Department of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany

Correspondence to: Martin Konrad MD, Department of Pediatrics, Philipps University, Deutschhausstrasse 12, D-35037 Marburg, Germany. Tel: +49 6421 2862789; Fax: +49 6421 2868956; E-mail: konradm@mailer.uni-marburg.de

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC, MIM 248250) is a complex renal tubular disorder characterised by hypomagnesaemia, hypercalciuria, advanced nephrocalcinosis, hyposthenuria and progressive renal failure. The mode of inheritance is autosomal recessive. A primary 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 linkage analysis in eight families, including three with consanguineous marriages. 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 recombination events reducing the critical interval to 6.6 cM. Recently, mutations in the gene PCLN-1, mapping to 3q27 and coding for paracellin-1, were identified by Simon et al (1999) as the underlying genetic defect in FHHNC. Paracellin-1 represents a renal tight junction protein predominantly expressed in the TAL. Mutational analysis in our patient cohort revealed eight different mutations in the PCLN-1 gene, within six novel mutations. In seven of 13 mutant alleles we detected a Leu151 substitution without evidence for a founder effect. Leu151 is a residue of the first extracellular loop of paracellin-1, the part of the protein expected to bridge the intercellular space and to be important for paracellular conductance. This study confirms the implication of paracellin-1 defects in FHHNC and points to a predominant role of this protein in the paracellular reabsorption of divalent cations in the TAL. European Journal of Human Genetics (2000) 8, 414-422.

hypomagnesaemia; hypercalciuria; nephrocalcinosis; renal failure; paracellin-1; PCLN-1