Skip to main content

Advertisement

Log in

A novel PCLN-1 gene mutation in familial hypomagnesemia with hypercalciuria and atypical phenotype

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Familial hypomagnesemic hypercalciuria and nephrocalcinosis (FHHNC [MIM 248250]) is a rare renal tubular disorder characterized by impaired reabsorption of magnesium and calcium in the thick ascending limb of Henle’s loop (tALH), causing renal magnesium wasting and hypercalciuria. Patients with FHHNC usually present with recurrent urinary tract infections, polyuria, nephrolithiasis (NL) and nephrocalcinosis (NC) with many progressing to chronic renal failure (CRF). We have shown recently that loss of function mutations in paracellin-1 PCLN-1/claudin-16, a renal tight junction protein located in the TAL, are causative of FHHNC. We present clinical and molecular studies on a highly inbred family with FHHNC in association with an unusual phenotype in that all affected members were extremely short. Affected individuals were found to be homozygous for marker D3S1314 on chromosome 3q. Sequencing of the PCLN-1/claudin-16 gene revealed a previously unknown point mutation at S235Y on exon 4 on the 4th transmembrane domain, providing additional evidence that inactivating mutations in the PCLN-1/claudin-16 gene result in FHHNC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Michelis MF, Drash AL, Linarelli LG, De Rubertis FR, Davis BB (1972) Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis. Metabolism 21:905–920

    Article  CAS  PubMed  Google Scholar 

  2. Manz F, Scharer K, Janka P, Lombeck J (1978) Renal magnesium wasting, incomplete tubular acidosis, hypercalciuria and nephrocalcinosis in siblings. Eur J Pediatr 128:67–79

    Article  CAS  PubMed  Google Scholar 

  3. Rodriguez-Soriano J, Vallo A (1994) Pathophysiology of the renal acidification defect in the syndrome of familial hypomagnesemia-hypercalciuria. Pediatr Nephrol 8:431–435

    Article  CAS  PubMed  Google Scholar 

  4. Benigno V, Canonica CS, Bettinelli A, von Vigier RO, Truttmann AC, Bianchetti MG (2000) Hypomagnesemia-hypercalciuria-nephrocalcinosis. A report of nine cases and a review. Nephrol Dial Transplant 15:605–610

    Article  CAS  PubMed  Google Scholar 

  5. Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari E, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP (1999) Paracellin-1, a renal tight junction protein required for paracellular Mg2+ reabsorption. Science 285:103–106

    Article  CAS  PubMed  Google Scholar 

  6. Weber S, Schneider L, Peters M, Misselwitz J, Ronnefarth G, Boswald M, Bonzel KE, Seeman T, Sulakova T, Kuwertz-Broking G, Gregoric A, Palcoux J-B, Tasic V, Manz F, Scharer K, Seyberth HW, Konrad M (2001) Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 12:1872–1881

    CAS  PubMed  Google Scholar 

  7. Praga M, Vara J, Gonzalez-Parra E, Andres A, Alamo C, Araque A, Ortiz A, Rodicio H (1995) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int 47:1419–1425

    Article  CAS  PubMed  Google Scholar 

  8. Blanchard A, Jeunemaitre X, Coudol P, Dechaux M, Froissart M, May A, Demontis R, Fournier A, Paillard M, Houillier P (2001) Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle. Kidney Int 59:2206–2215

    Article  CAS  PubMed  Google Scholar 

  9. Haffner D, Weifurth A, Manz F, Schmidt H, Bremer HJ, Mehls O, Scharer K (1999) Long-term outcome of pediatric patients with hereditary tubular disorders. Nephron 83:250–260

    Article  CAS  PubMed  Google Scholar 

  10. Wolf MTF, Dotsch J, Konrad M, Boswald M, Rascher M (2002) Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene. Pediatr Nephrol 17:602–608

    Article  PubMed  Google Scholar 

  11. Blaschke RJ, Monaghan AP, Schiller S, Schechinger B, Rao E, Padilla-Nash H, Ried T, Rappold GA (1998) SHOT, a SHOX- related homeobox gene, is implicated in craniofacial, brain, heart, and limb development. Proc Nat Acad Sci 95:2406–2411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton M-P, Groselle D, de Kerdanet M, Kadiri A, Epelbaum J, Le Bloc Y, Amselem S (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 116:760–768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wrong O (1998) Nephrocalcinosis. In: Davidson AM, Grunfeld JP, Kerr DNS, Ritz E, Winearls CG (eds) Oxford textbook of clinical nephrology, 2nd edn. Oxford University Press, Oxford, pp 1376–1396

    Google Scholar 

  14. Hirano T, Kobayashi N, Itoh T, Takasuga A, Nakamuru T, Hirotsune S, Sugimoto Y (2000) Novel mutations of PCLN-1/claudin-16 results in bovine chronic interstitial nephritis. Genome Res 10:659–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ohba Y, Kitagawa H, Kitoh S, Sasaki Y, Takami M, Shinkai Y, Kunieda T (2000) A deletion of the paracellin-1 gene is responsible for renal tubular dysplasia in cattle. Genomics 68:229–236

    Article  CAS  PubMed  Google Scholar 

  16. Muller D, Kausalya PJ, Claverie-Martin F, Meij IC, Eggert P, Garcia-Nieto V, Hunziker W (2003) A novel claudin16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting. Am J Hum Genet 73:1293–1301

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sami A. Sanjad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanjad, S.A., Hariri, A., Habbal, Z.M. et al. A novel PCLN-1 gene mutation in familial hypomagnesemia with hypercalciuria and atypical phenotype. Pediatr Nephrol 22, 503–508 (2007). https://doi.org/10.1007/s00467-006-0354-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-006-0354-5

Keywords

Navigation