CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder caused by CLDN16 mutations. CLDN16 encodes the renal tight junction protein claudin-16, which is important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle's loop. That FHHNC is frequently associated with progressive renal failure suggests additional roles for claudin-16 in the maintenance of tight junction integrity. An investigation of 32 patients with FHHNC and 17 different mutations was previously reported; here, the analysis is expanded to 39 additional patients and 12 new mutations. Expression studies revealed that five of the 12 new mutations led to partial loss of claudin-16 function and the remaining seven led to complete loss of function. The 23 patients who had mutations resulting in complete loss of function of both alleles were significantly younger at the onset of symptoms than the 46 patients who had at least one mutant allele providing partial function (2.2 versus 5.6 years; P Ͻ 0.01). In addition, those with complete loss of function had a more rapid decline in GFR (7.3 versus 2.9 ml/min per 1.72 m 2 /y; P Ͻ 0.01), leading to 54% requiring renal replacement therapy by age 15 compared with 20% of those with residual function (P Ͻ 0.05). These data suggest that residual function of claudin-16 may delay the progression of renal failure in FHHNC.

Renal, Ocular, and Neuromuscular Involvements in Patients with CLDN19 Mutations

“…First, although FHHNC is mostly diagnosed during the first years of life (age of diagnosis within the first decade for all patients, within the first year of life for 8 of 12 patients) (5), it can be asymptomatic until the end of the second decade as exemplified by patient F2.3. In patients with CLDN16-related FHHNC, a genotype-phenotype correlation has been established and age at onset and severity may be predicted from the CLDN16 genotype (12). Because of the recent recognition of CLDN19 mutations in humans and their low frequency, this analysis has not yet been performed in patients with CLDN19 mutations.…”

“…FHHNC may be disclosed by a wide variety of symptoms, including recurrent urinary tract infection, polyuria and/or polydipsia, nephrolithiasis, or tetanic convulsions (11). In patients with CLDN16 mutations, progression to ESRD may be predicted by the genotype (12). Of note, Konrad et al emphasized the severe ocular involvement (macular colobomata, nystagmus, myopia, visual loss) shown in CLDN19 contrasting with the mild ocular involvement in some CLDN16 patients (myopia, astygmatism, hypermetropia, strabism) (5,10).…”

Biology of claudins

“…At least 30 different claudin-16 mutations have now been reported in families with FHHNC (13, 56, 60, 65, 66, 76 -78, 88, 91, 94, 95, 100, 110, 111). Several are predicted to prematurely truncate the protein, and many have been shown to cause defects in trafficking of the protein to the plasma membrane (44,57,60). These findings suggested that claudin-16 might function as a divalent cation-selective paracellular pore and that FHHNC could be due to loss-of-function mutations that would be expected to abolish paracellular P Ca and P Mg in the TALH.…”

Lecture

“…23 Many different FHHNC mutations have been identified in the human CLDN16 gene. 48,49 The expression of CLDN16 is restricted to the thick ascending limb (TAL) of the nephron. 23 We transfected a renal model cell line LLC-PK1 with CLDN16 and found a large increase in Na + permeability (P Na ) accompanied by an only moderately enhanced Mg 2+ permeability (P Mg ).…”