title: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Département de Génétique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Astrid
authors.initials: A
authors.lastname: Godron
authors.forename: Jérôme
authors.initials: J
authors.lastname: Harambat
authors.forename: Valérie
authors.initials: V
authors.lastname: Boccio
authors.forename: Anne
authors.initials: A
authors.lastname: Mensire
authors.forename: Adrien
authors.initials: A
authors.lastname: May
authors.forename: Claire
authors.initials: C
authors.lastname: Rigothier
authors.forename: Lionel
authors.initials: L
authors.lastname: Couzi
authors.forename: Benoit
authors.initials: B
authors.lastname: Barrou
authors.forename: Michel
authors.initials: M
authors.lastname: Godin
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
authors.forename: Stanislas
authors.initials: S
authors.lastname: Faguer
authors.forename: Marion
authors.initials: M
authors.lastname: Vallet
authors.forename: Pierre
authors.initials: P
authors.lastname: Cochat
authors.forename: Philippe
authors.initials: P
authors.lastname: Eckart
authors.forename: Geneviève
authors.initials: G
authors.lastname: Guest
authors.forename: Vincent
authors.initials: V
authors.lastname: Guigonis
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Rosa
authors.initials: R
authors.lastname: Vargas-Poussou
mesh_terms: D000293:Adolescent; D000328:Adult; D044383:Black People / Q000235:genetics; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D057167:Claudins / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D005124:Eye Abnormalities / Q000150:complications / Q000235:genetics*; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D053565:Hypercalciuria / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D007223:Infant; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000235:genetics; D008297:Male; D009154:Mutation; D009397:Nephrocalcinosis / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D015499:Renal Tubular Transport, Inborn Errors / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D012189:Retrospective Studies; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C508912:CLDN19 protein, human; D057167:Claudins; C502010:claudin 16