Article Figures & Data
Figures
- Figure 1.
(A) Genomic organization of CLDN16. Mutations are depicted above the schematic presentation of CLDN16 (novel mutations in bold). (B) Claudin-16 protein model deduced from hydrophilicity plots. Amino acid residues affected by novel missense mutations are underlined. CL mutations are depicted in black; PL mutations are depicted in gray.
- Figure 2.
CLDN16 mutations resulting in trafficking defects. Epifluorescence images showing mistargeted localization of claudin-16 mutants in LLC-PK1 and MDCK cells. M71T is in the lysosome with a punctuate distribution toward periphery of the cell. C131R shows a reticular cytoplasmic and perinuclear distribution indicating retention in the endoplasmic reticulum. Bar = 10 μm.
- Figure 3.
Dilution potential of individual CLDN16 missense mutations after heterologous expression in LLC-PK1 cells. Values are given as percentage relative to wild-type claudin-16 function. New mutations are underlined; the remaining mutations were taken from Hou et al.22 WT, wild-type.
- Figure 4.
(A) Age at manifestation of first clinical symptoms. (B) Progression of renal failure expressed as loss of GFR (ml/min per 1.73 m2/yr). Data are means ± SEM, ANOVA was performed only between the groups with categorized mutations on both alleles. *P < 0.05; **P < 0.01.
- Figure 5.
Progression of renal failure over time in FHHNC according to the mutation category. Data are means ± SEM.
- Figure 6.
Serum intact PTH levels with corresponding GFR in patients with FHHNC and control subjects. Normal range is indicated in gray.
Tables
Patient Gender Origin Consanguinity Zygosity Nucleotide Change Predicted Protein Change F29 F German − Homozygous 453(TTG→TTT) p.L151F F30 F German − Homozygous 453(TTG→TTT) p.L151F F32-1 M Turkish + Homozygous 715(GGA→AGA) p.G239R F32-2 M Turkish + Homozygous 715(GGA→AGA) p.G239R F33 M German − Homozygous 453(TTG→TTT) p.L151F F34 F German − Compound heterozygous 385(CGC→TGC)-453(TTG→TTT) p.R129Ca-p.L151F F37-1 M German − Heterozygous 453(TTG→TTT) p.L151F F37-2 M German − Heterozygous 453(TTG→TTT) p.L151F F56 F ? + Homozygous 341(CGA→AGA) p.R114Qa F60 F German − Compound heterozygous 453(TTG→TTT)-625(GCT→ACT) p.L151F-p.A209T F61-1 M German − Heterozygous 453(TTG→TTT) p.L151F F61-2 F German − Heterozygous 453(TTG→TTT) p.L151F F62 M Arab + Homozygous 236delG p.A80fsX91a F64 F Polish − Compound heterozygous 329(AGC→AGG)-453(TTG→TTT) p.L151F-p.S110Ra F66 M Turkish + Homozygous 710(TGG→TAG) p.W237Xa F63-1 M British − Compound heterozygous 646(CGT→TGT)-784 + 1(G→T) p.R216C-splice sitea F69-2 F British − Compound heterozygous 646(CGT→TGT)-784 + 1(G→T) p.R216C-splice sitea F70 F Turkish + Homozygous 679(GGA→CGA) p.G227Ra F71 M Bulgarian − Compound heterozygous 434(CTG→CCG)- 453(TTG→TTT) p.L145P-p.L151F F72 F English/German − Compound heterozygous 408–410delCAT-453(TTG→TTT) p.I137dela-p.L151F F73 F German − Heterozygous 385(CGC→TGC) p.R129Ca-? F74-1 M Serbian − Homozygous 453(TTG→TTT) p.L151F F74-2 F Serbian − Homozygous 453(TTG→TTT) p.L151F F74-3 M Serbian − Homozygous 453(TTG→TTT) p.L151F F77 M German − Compound heterozygous 453(TTG→TTT)-263(GGG→GAG) p.L151F-p.G88E F78-1 M Arab + Homozygous 212(ATG→ACG) p.M71T,a loss of start F79-1 F Arab + Homozygous 212(ATG→ACG) p.M71T,a loss of start F80-1 F Arab + Homozygous 212(ATG→ACG) p.M71T,a loss of start F80-2 F Arab + Homozygous 212(ATG→ACG) p.M71T,a loss of start F80-3 M Arab + Homozygous 212(ATG→ACG) p.M71T,a loss of start F81-1 F Arab + Homozygous 646(CGT→TGT) p.R216Ca F81-2 M Arab + Homozygous 646(CGT→TGT) p.R216Ca F83-1 F Macedonian + Homozygous 453(TTG→TTT) p.L151F F83-2 F Macedonian + Homozygous 453(TTG→TTT) p.L151F F83-3 M Macedonian + Homozygous 453(TTG→TTT) p.L151F F87-1 M Turkish + Homozygous 453(TTG→TTT) p.L151F F87-2 M Turkish + Homozygous 453(TTG→TTT) p.L151F F87-3 M Turkish + Homozygous 453(TTG→TTT) p.L151F F88-1 M Turkish + Homozygous 385(CGC→TGC) p.C131Ra ↵a New mutation.
Mutation Position TER Dilution Potential PNa/PCl PNa (10−6 cm/s) PCl (10−6 cm/s) Localization Function Vector — 61.0 ± 2.1 −8.13 ± 0.19b 0.296 ± 0.010b 6.866 ± 0.184b 23.220 ± 0.182 − − WT — 33.0 ± 1.5 2.97 ± 0.19 1.500 ± 0.038 33.363 ± 0.346 22.257 ± 0.346 TJ + M71T N terminus 60.0 ± 2.5 −7.83 ± 0.12b 0.313 ± 0.007b 7.282 ± 0.121b 23.307 ± 0.123 Lysosome CL G88E First TMD 50.7 ± 2.9 −7.13 ± 0.09b 0.354 ± 0.005b 9.398 ± 0.105b 26.590 ± 0.106 TJ CL S110R First ECL 38.3 ± 0.9 −3.30 ± 0.12b 0.637 ± 0.010b 18.787 ± 0.188b 29.513 ± 0.188 TJ PL R114Q First ECL 34.7 ± 3.7 −2.33 ± 0.09b 0.728 ± 0.009b 22.100 ± 0.153b 30.340 ± 0.153 TJ PL C131R First ECL 60.7 ± 3.0 −7.50 ± 0.06b 0.332 ± 0.003b 7.493 ± 0.057b 22.597 ± 0.055 ER CL I137del First ECL 41.7 ± 2.3 −4.57 ± 0.09b 0.530 ± 0.007b 15.143 ± 0.130b 28.557 ± 0.130 TJ PL H141D First ECL 39.3 ± 2.6 −3.17 ± 0.09b 0.649 ± 0.008b 18.513 ± 0.141b 28.547 ± 0.141 TJ PL L151W First ECL 39.7 ± 0.9 −1.97 ± 0.18b 0.766 ± 0.018b 19.903 ± 0.271b 25.983 ± 0.273 TJ PL R216C Second ECL 44.3 ± 2.7 −5.10 ± 0.20b 0.490 ± 0.015b 13.710 ± 0.280b 28.003 ± 0.277 TJ CL G227R Second ECL 39.0 ± 1.0 −3.20 ± 0.06b 0.646 ± 0.005b 18.460 ± 0.092b 28.600 ± 0.092 TJ PL Patient Gender Predicted Change Predicted Function Patient Gender Predicted Change Predicted Function Allele 1 Allele 2 Allele 1 Allele 2 F03 F p.G198D p.G198D CL/CL F02-1 F p.L151F p.L151W PL/PL F04 F p.G239R p.G239R CL/CL F02-2 M p.L151F p.L151W PL/PL F09-1 F p.R216T p.R216T CL/CL F07-1 M p.L151F p.L151F PL/PL F09-2 M p.R216T p.R216T CL/CL F07-2 M p.L151F p.L151F PL/PL F10 F p.L145P p.L145P CL/CL F08-1 M p.H141D p.H141D PL/PL F11 F p.G239R p.G239R CL/CL F08-2 F p.H141D p.H141D PL/PL F15 F p.R149L p.R149L CL/CL F13 M p.L151F p.L151F PL/PL F21-1 M p.L145P p.D123fs CL/CL F14-1 F p.L151F p.L151F PL/PL F21-2 F p.L145P p.D123fs CL/CL F14-2 F p.L151F p.L151F PL/PL F32-1 M p.G239R p.G239R CL/CL F17 F p.L151F p.L151F PL/PL F32-2 M p.G239R p.G239R CL/CL F18 F p.L151F p.L151F PL/PL F62 M p.A80fsX91 p.A80fsX91 CL/CL F22 F p.L151F p.L151F PL/PL F66 M p.W237X p.W237X CL/CL F25 M p.L151F p.L151F PL/PL F69-1 M p.R216C Splice site CL/CL F29 F p.L151F p.L151F PL/PL F69-2 F p.R216C Splice site CL/CL F30 F p.L151F p.L151F PL/PL F78-1 M p.M71Ta p.M71Ta CL/CL F33 M p.L151F p.L151F PL/PL F79-1 F p.M71Ta p.M71Ta CL/CL F56 F p.R114Q p.R114Q PL/PL F80-1 F p.M71Ta p.M71Ta CL/CL F60 F p.L151F p.A209T PL/PL F80-2 F p.M71Ta p.M71Ta CL/CL F64 F p.L151F p.S110R PL/PL F80-3 M p.M71Ta p.M71Ta CL/CL F70 F p.G227R p.G227R PL/PL F81-1 F p.M71Ta p.M71Ta CL/CL F74-1 M p.L151F p.L151F PL/PL F81-2 M p.M71Ta p.M71Ta CL/CL F74-2 F p.L151F p.L151F PL/PL F88-1 M p.C131R p.C131R CL/CL F74-3 M p.L151F p.L151F PL/PL F83-1 F p.L151F p.L151F PL/PL F01-1 F p.L151F p.W117X PL/CL F83-2 F p.L151F p.L151F PL/PL F01-2 F p.L151F p.W117X PL/CL F83-3 M p.L151F p.L151F PL/PL F05-1 F p.L151F p.L145P PL/CL F87-1 M p.L151F p.L151F PL/PL F05-2 F p.L151F p.L145P PL/CL F87-2 M p.L151F p.L151F PL/PL F06 M p.L151F p.G239R PL/CL F87-3 M p.L151F p.L151F PL/PL F12 M p.A209T p.L145P PL/CL F16 F p.L151F Splice site PL/CL F34 F p.R129C p.L151F PL/X F20 M p.L151F p.L145P PL/CL F37-1 M p.L151F ? PL/X F23 M p.L151F p.S235P PL/CL F37-2 M p.L151F ? PL/X F71 M p.L151F p.L145P PL/CL F61-1 M p.L151F ? PL/X F72 F p.L151F p.I137del PL/CL F61-2 F p.L151F ? PL/X F77 M p.L151F p.G88Q PL/CL F19 M Splice site ? CL/X ↵a Loss of translation start site.
Genotype CL/CL (n = 23) PL/PL (n = 29) PL/CL (n = 12) PL/X (n = 5) Age at onset (yr; mean [95% CI]) 2.2 (1.1 to 3.3) 5.7 (3.3 to 8.2)a 4.9 (2.3 to 7.6) 5.9 (2.6 to 9.2) Loss of GFR/yr (ml/min per 1.73 m2; mean [95% CI]) 7.3 (5.0 to 9.6) 3.3 (1.6 to 4.9)b 3.0 (1.1 to 4.9)a 2.9 (1.6 to 4.1) Renal function at end of study GFR >60 ml/min per 1.73 m2 9% (2/22) 55% (16/29)b 5/12 4/5 GFR <60 ml/min per 1.73 m2 50% (11/22) 17% (5/29)b 3/12 1/5 ESRD 41% (9/22) 18% (8/29)b 4/12 0/5 ESRD at 15 yr 54% (7/13) 25% (5/20) 1/10 ESRD at 20 yr 70% (7/10) 36% (5/14) 3/6 Genotype CL (n = 23) PL (n = 46) P Age at onset (yr; mean [95% CI]) 2.2 (1.1 to 3.3) 5.6 (3.6 to 7.0) <0.01 Loss of GFR/yr (ml/min per 1.73 m2; mean [95% CI]) 7.3 (5.0 to 9.6) 2.9 (1.8 to 4.3) <0.01 Renal function at end of study <0.01 GFR >60 ml/min per 1.73 m2 9% (2/22) 54% (25/46) GFR <60 ml/min per 1.73 m2 50% (11/22) 20% (9/46) ESRD 41% (9/22) 26% (12/46) ESRD at 15 yr 54% (7/13) 20% (6/30) <0.05 ESRD at 20 yr 70% (7/10) 25% (8/20) NS Lowest serum Mg (mmol/L; mean [95% CI]) 0.40 (0.35 to 0.45) 0.41 (0.38 to 0.45) NS Urinary Mg excretion (μ mol/kg per d; mean [95% CI]) 188 (92 to 283) 153 (123 to 183) NS Lowest serum Ca (mmol/L; mean [95% CI]) 2.11 (1.96 to 2.27) 2.17 (2.1 to 2.25) NS Urinary Ca excretion (μ mol/kg per d; mean [95% CI]) 314 (181 to 446) 200 (168 to 233) <0.01 Urinary Ca/creatinine (mol/mol; mean [95% CI]) 2.46 (1.37 to 3.55) 1.52 (1.26 to 1.79) <0.05 Intact PTH (pg/ml; mean [95% CI]) 249 (122 to 376) 169 (117 to 220) NS Follow-up time (yr; mean [95% CI]) 13.4 (9.2 to 17.6) 11.9 (9.2 to 14.7) NS
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CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis
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