A novel claudin-16 mutation, severe bone disease, and nephrocalcinosis

Nadarajah, Luxme; Khosravi, Maryam; Dumitriu, Simona; Klootwijk, Enriko; Kleta, Robert; Yaqoob, Muhammad; Walsh, Stephen B.

doi:10.1016/s0140-6736(13)62673-2

Cited by 9 publications

(10 citation statements)

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“…Cldn16 is required for renal calcium and magnesium reabsorption as evident from patients with rare mutations in claudin 16 [39,40,41]. Thus, in theory, loss of Ae3 in the TAL may affect Cldn16 expression and function and stimulate the expression of Trpv5 and Trpm6 expression and function in the late distal convoluted tubule and connecting tubule.…”

Section: Discussionmentioning

confidence: 99%

The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

Kampik

Gehring

Schnitzbauer

et al. 2014

Cell Physiol Biochem

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Background: The Slc4 family of bicarbonate transporters consists of several members, many of which are highly expressed in the kidney and play an important role in acid-base homeostasis. Among them are Ae1 (Slc4a1) and Ae2 (Slc4a2). Another member, Ae3 (Slc4a3), is suggested to be expressed in the kidney, however, its localization and impact on renal function is still unknown. Ae3 has also been implicated in the central control of breathing. Aims: Here, we analyzed the expression of Ae3 transcripts in isolated nephron segments and investigated systemic and renal acid-base homeostasis and renal electrolyte handling in the absence of Ae3, using a knock out mouse model. Methods: qPCR was used to localize Ae3 transcripts in the murine nephron, metabolic studies and whole body plethysmography to assess the role of Ae3 in renal functions. Results: Two Ae3 transcripts, the brain variant bAe3 and the cardiac variant cAe3, are expressed at low levels in the murine kidney. Although differentially distributed, they localize mostly to the distal nephron and renal collecting duct system. At baseline and after an acid challenge, mice deficient for Ae3 did not show major disturbances in renal acid-base excretion. Respiratory responses in whole body plethysmography to acid loading and CO2 and O2 challenges were normal. No major differences in renal electrolyte handling were discovered except for small changes in magnesium, potassium and sodium excretion after 7 days of acid loading. We therefore challenged mice with diets with high and low magnesium diets and found no differences in renal magnesium excretion but elevated expression of the Trpm6 magnesium channel in Ae3 KO mice. In conclusion, Ae3 is expressed in murine kidney at very low levels. Conclusions: Ae3 plays no role in systemic acid-base homeostasis but may modify renal magnesium handling inducing a higher expression of Trpm6.

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Section: Discussionmentioning

confidence: 99%

The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

Kampik

Gehring

Schnitzbauer

et al. 2014

Cell Physiol Biochem

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“…Among mentioned pathologies, hyperoxaluria, Dent's disease and FHHNC are associated with ESRD. 2,3 Thus, FHHNC should be considered and other laboratory parameters should be detected while evaluating patients with medullary nephrocalcinosis even in the neonatal period.…”

Section: Discussionmentioning

confidence: 99%

“…It seems to be clustered at 2-3 years of age. 2,4,5,[11][12][13][14][15][16] This relatively late age of diagnosis indicates that clinicians are not aware of this entity. Strikingly, our patients were diagnosed in an early period of their lives.…”

Section: Discussionmentioning

confidence: 99%

“…1 In comparison to distal renal tubular acidosis (dRTA), medullary sponge kidney and primary hyperparathyroidism which are also characterized by medullary nephrocalcinosis, FHHNC is a devastating condition leading to end-stage renal disease (ESRD). 2 Mutations in the CLDN genes (CLDN- [16][17][18][19], encoding renal tight junction proteins (claudin-16 and claudin-19) playing key roles in magnesium handling in the thick ascending limb of Henle's loop, result in FHHNC. Both mutations cause a similar renal phenotype and CLDN19 mutations result in additional ocular involvement.…”

Section: Abstract: Nephrocalcinosis Hypomagnesemia Hypercalciuriamentioning

confidence: 99%

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A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings

et al. 2018

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Alparslan C, Öncel EP, Akbay S, Alaygut D, Mutlubaş F, Tatlı M, Konrad M, Yavaşcan Ö, Kasap-Demir B. A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings. Turk J Pediatr 2018; 60: 76-80. Familial hypomagnesemic hypercalciuric nephrocalcinosis (FHHNC) (OMIM: 248250) is characterized by hypomagnesemia, hypercalciuria and nephrocalcinosis. FHHNC inevitably progresses to end-stage renal disease in decades. Mutations in CLDN-16 and CLDN-19 genes are associated with disrupted magnesium handling in the thick ascending limp of Henle`s loop. Patients with mutations in these genes share similar clinical features, and those with CLDN-19 gene mutations have ocular findings in addition. A 2-month-old boy, was admitted to our clinic with the complaints of upper respiratory tract infection. He was the first-born child of consanguineous parents. Laboratory findings revealed hypocalcemia and hypomagnesemia. Bilateral medullary nephrocalcinosis was detected on abdominal ultrasound. His ophthalmologic examination was unremarkable. With hypomagnesemia, hypercalciuria and nephrocalcinosis, the patient was considered to have FHHNC. Oral magnessium supplementation was initiated. Four years of follow-up has been completed uneventfully. When 6-days-old the brother of the case above was admitted with seizure. The patient was resistant to calcium and anticonvulsant drugs and the seizure activity could only be controlled after magnesium infusion. Biochemistry profile revealed hypocalcemia and hypomagnesemia. Urinary calcium extraction was 11 mg/kg/day. Medullary nephrocalcinosis was reported on renal ultrasound. His eye examination, echocardiography, transfontanel ultrasound and electroencephalography were normal. Due to the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis, and the medical history of his elder brother, he was diagnosed with FHHNC. After correction of the electrolyte abnormalities, he was discharged from hospital and is currently being followed-up without any problem. In this manuscript, we shared our experience about a novel homozygous mutation (W99C) in CLDN-16 gene causing FHHNC in a couple of Turkish siblings.

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“…Bone disease [74], bone deformities [62], failure to thrive [50][51][52]62,75] and rickets [45,52,62,76] are reported but their exact pathophysiological mechanisms need to be elucidated.…”

Section: Phenotypementioning

confidence: 99%

Claudins in Renal Physiology and Pathology

Prot-Bertoye

Houillier

2020

Genes

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Claudins are integral proteins expressed at the tight junctions of epithelial and endothelial cells. In the mammalian kidney, every tubular segment express a specific set of claudins that give to that segment unique properties regarding permeability and selectivity of the paracellular pathway. So far, 3 claudins (10b, 16 and 19) have been causally traced to rare human syndromes: variants of CLDN10b cause HELIX syndrome and variants of CLDN16 or CLDN19 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The review summarizes our current knowledge on the physiology of mammalian tight junctions and paracellular ion transport, as well as on the role of the 3 above-mentioned claudins in health and disease. Claudin 14, although not having been causally linked to any rare renal disease, is also considered, because available evidence suggests that it may interact with claudin 16. Some single-nucleotide polymorphisms of CLDN14 are associated with urinary calcium excretion and/or kidney stones. For each claudin considered, the pattern of expression, the function and the human syndrome caused by pathogenic variants are described.

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A novel claudin-16 mutation, severe bone disease, and nephrocalcinosis

Cited by 9 publications

References 2 publications

The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings

Claudins in Renal Physiology and Pathology

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A novel claudin-16 mutation, severe bone disease, and nephrocalcinosis

Cited by 9 publications

References 2 publications

The Murine Cl-/HCO3-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

The Murine Cl-/HCO3-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings

Claudins in Renal Physiology and Pathology

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Product

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The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney

The Murine Cl^-/HCO₃^-Exchanger Ae3 (Slc4a3) is Not Required for Acid-Base Balance but is Involved in Magnesium Handling by the Kidney