Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations.

BACKGROUND AND OBJECTIVES Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed. RESULTS Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression. CONCLUSIONS Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.

[1]  J. Hou,et al.  Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. , 2008, The Journal of clinical investigation.

[2]  I. Narama,et al.  Renal dysplasia unrelated to claudin-16 deficiency in Japanese Black cattle. , 2007, Journal of comparative pathology.

[3]  Yan Luo,et al.  Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium , 2011, Progress in Retinal and Eye Research.

[4]  Stephan C F Neuhauss,et al.  Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. , 2006, American journal of human genetics.

[5]  宮本 達雄.  Tight junctions in Schwann cells of peripheral myelinated axons : a lesson from claudin-19 deficient mice , 2007 .

[6]  Z. Abassi,et al.  Double gene deletion reveals lack of cooperation between claudin 11 and claudin 14 tight junction proteins , 2008, Cell and Tissue Research.

[7]  S. Hirotsune,et al.  A new deletion mutation in bovine Claudin-16 (CL-16) deficiency and diagnosis. , 2002, Animal genetics.

[8]  R. V. von Vigier,et al.  Hypomagnesaemia-hypercalciuria-nephrocalcinosis: a report of nine cases and a review. , 2000, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[9]  K. Okada,et al.  Abnormal development of nephrons in claudin-16-defective Japanese black cattle. , 2005, The Journal of veterinary medical science.

[10]  M. Nagel,et al.  Familial hypomagnesemia with hypercalciuria and nephrocalcinosis in three siblings having the same genetic lesion but different clinical presentations , 2012, World Journal of Pediatrics.

[11]  N. Kobayashi,et al.  Null mutation of PCLN-1/Claudin-16 results in bovine chronic interstitial nephritis. , 2000, Genome research.

[12]  Bjarni V. Halldórsson,et al.  Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density , 2009, Nature Genetics.

[13]  H. Kitagawa,et al.  Pathological changes of renal tubular dysplasia in Japanese Black cattle , 2002, Veterinary Record.

[14]  R. Bindels,et al.  Great strides in the understanding of renal magnesium and calcium reabsorption. , 2000, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[15]  M. F. Michelis,et al.  Decreased bicarbonate threshold and renal magnesium wasting in a sibship with distal renal tubular acidosis. (Evaluation of the pathophysiological role of parathyroid hormone). , 1972, Metabolism: clinical and experimental.

[16]  N. Fullwood,et al.  Tight junction-related protein expression and distribution in human corneal epithelium. , 2003, Experimental eye research.

[17]  L. Desjardins,et al.  Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF , 2004, Human mutation.

[18]  A. Yu,et al.  Biology of claudins. , 2008, American journal of physiology. Renal physiology.

[19]  Tom Greene,et al.  Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. , 2007, Clinical chemistry.

[20]  V. Tasic,et al.  Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. , 2001, Journal of the American Society of Nephrology : JASN.

[21]  P. Houillier,et al.  Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle. , 2001, Kidney international.

[22]  R. Lifton,et al.  Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. , 1999, Science.

[23]  M. Konrad,et al.  The role of tight junctions in paracellular ion transport in the renal tubule: lessons learned from a rare inherited tubular disorder. , 2011, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[24]  S. Gallati,et al.  CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. , 2008, Journal of the American Society of Nephrology : JASN.

[25]  X. Jeunemaître,et al.  Report of a family with two different hereditary diseases leading to early nephrocalcinosis , 2008, Pediatric Nephrology.

[26]  Tom Greene,et al.  Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate (Annals of Internal Medicine (2006) 145, (247-254)) , 2008 .

[27]  M. Fromm,et al.  Claudins of intestine and nephron – a correlation of molecular tight junction structure and barrier function , 2011, Acta physiologica.

[28]  R. Adelman,et al.  Claudin-19 and the barrier properties of the human retinal pigment epithelium. , 2011, Investigative ophthalmology & visual science.

[29]  Susan L Furth,et al.  New equations to estimate GFR in children with CKD. , 2009, Journal of the American Society of Nephrology : JASN.

[30]  J. Hou,et al.  Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium , 2009, Proceedings of the National Academy of Sciences.

[31]  L. Rostaing,et al.  Renal, ocular, and neuromuscular involvements in patients with CLDN19 mutations. , 2011, Clinical journal of the American Society of Nephrology : CJASN.