The Case | Renal tubular acidosis and eye findings

Kari, Jameela A.; Desoky, Sherif M. El; Singh, Ajay K.; Gari, Mamdooh; Kleta, Robert; Böckenhauer, Detlef

doi:10.1038/ki.2013.320

Cited by 20 publications

(10 citation statements)

References 3 publications

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“…Missense mutations make up the greatest proportion and include p.Arg298Ser (Igarashi et al 1999(Igarashi et al , 2002, p.Ser427Leu (Dinour et al 2004), p.Thr485Ser (Horita et al 2005), p.Gly486Arg (Suzuki et al 2008), p.Arg510His (Igarashi et al 1999;Shiohara et al 2000;Suzuki et al 2010), p.Leu522Pro (Demirci et al 2006, p.Ala799Val (Horita et al 2005) and p.Arg881Cys (Horita et al 2005;Suzuki et al 2010). The remainder include two nonsense mutations, p.Gln29X (Igarashi et al 2001) and p.Trp516X (Lo et al 2011); two frame-shift mutations, p.Asn721ThrfsX30 (Inatomi et al 2004) and p.Ser982AsnfsX4 (Suzuki et al 2010); and one deletion mutation, p.Leu738del (Kari et al 2014).…”

Section: Introductionmentioning

confidence: 99%

A novel mutant Na⁺/HCO3⁻ cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

Myers

Yuan

Felmlee

et al. 2016

The Journal of Physiology

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Proximal renal tubular acidosis (pRTA) is a rare, recessively-inherited disease characterized by abnormally acidic blood, blindness, as well as below average height and weight. pRTA is typically associated with homozygous mutation of the solute carrier 4 family gene SLC4A4. SLC4A4 encodes the electrogenic sodium bicarbonate cotransporter NBCe1, a membrane protein that acts to maintain intracellular and plasma pH. We present the first description of a case of compound-heterozygous inheritance of pRTA. The individual has inherited two mutations in NBCe1: p.Arg510His (R510H) and p.Gln913Arg (Q913R), one from each parent. In addition to the usual features of pRTA, the patient exhibits unusual signs, such as muscle spasms and fever. We have recreated these mutant transporters for expression in model systems. We find that both of the mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. When expressed in Xenopus oocytes, we find that the R510H and Q913R-mutant NBCe1 molecules exhibit apparently normal Na /HCO cotransport activity but that Q913R is associated with an unusual HCO independent anion-leak. We conclude that a reduced accumulation of NBCe1 protein in the basolateral membrane of proximal-tubule epithelia is the most probable cause of pRTA in this case. We further note that the Q913R-associated anion-leak could itself be pathogenic if expressed in the plasma membrane of mammalian cells, compromising the benefit of strategies aiming to enhance mutant NBCe1 accumulation in the plasma membrane.

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Section: Introductionmentioning

confidence: 99%

A novel mutant Na⁺/HCO3⁻ cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

Myers

Yuan

Felmlee

et al. 2016

The Journal of Physiology

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“…Pathogenic mutations in the SLC4A4 gene encoding for the basolateral electrogenic sodium-bicarbonate cotransporter NBCe1 cause proximal renal tubular acidosis with ocular abnormalities and mental retardation (OMIM #604278, table 1) 54,55 . Patients often present with growth retardation and short stature, metabolic acidosis with low bicarbonate, mental retardation, teeth enamel defects, and bilateral glaucoma, cataracts, and band keratopathy 56 . Since proximal tubular bicarbonate transport is impaired the threshold for bicarbonate reabsorption is reduced and can be tested using an alkali-loading test restoring plasma bicarbonate levels to normal.…”

Section: Gene Defects Underlying Proximal Renal Tubular Acidosis (Prtmentioning

confidence: 99%

Molecular Pathophysiology of Acid-Base Disorders

Wagner

Silva

Bourgeois

2019

Seminars in Nephrology

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Acid-base balance is critical for normal life. Acute and chronic disturbances impact cellular energy metabolism, endocrine signaling, ion channel activity, neuronal activity, and cardiovascular functions such as cardiac contractility and vascular blood flow. Maintenance and adaptation of acid-base homeostasis are mostly controlled by respiration and kidney. The kidney contributes to acid-base balance by reabsorbing filtered bicarbonate, regenerating bicarbonate through ammoniagenesis and generation of protons, and by excreting acid. This review focuses on acid-base disorders caused by renal processes, both inherited and acquired. Distinct rare inherited monogenic diseases affecting acid-base handling in the proximal tubule and collecting duct have been identified. In the proximal tubule, mutations of solute carrier 4A4 (SLC4A4) (electrogenic Na/HCO-cotransporter Na/bicarbonate cotransporter e1 [NBCe1]) and other genes such as CLCN5 (Cl/H-antiporter), SLC2A2 (GLUT2 glucose transporter), or EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) causing more generalized proximal tubule dysfunction can cause proximal renal tubular acidosis resulting from bicarbonate wasting and reduced ammoniagenesis. Mutations in adenosine triphosphate ATP6V1 (B1 H-ATPase subunit), ATPV0A4 (a4 H-ATPase subunit), SLC4A1 (anion exchanger 1), and FOXI1 (forkhead transcription factor) cause distal renal tubular acidosis type I. Carbonic anhydrase II mutations affect several nephron segments and give rise to a mixed proximal and distal phenotype. Finally, mutations in genes affecting aldosterone synthesis, signaling, or downstream targets can lead to hyperkalemic variants of renal tubular acidosis (type IV). More common forms of renal acidosis are found in patients with advanced stages of chronic kidney disease and are owing, at least in part, to a reduced capacity for ammoniagenesis.

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“…However, except for occasional case reports and case series, very little new data are available for these very rare disorders. 28,29 Clinical Controversies Patients with FRTS exhibit proteinuria. This primarily reflects "tubular" proteinuria, i.e., the impaired reabsorption of filtered proteins, but in some patients proteinuria reaches the nephrotic range.…”

Section: Ptmentioning

confidence: 99%

Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial?

Kleta

Böckenhauer

2017

JASN

Self Cite

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Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.

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The Case | Renal tubular acidosis and eye findings

Cited by 20 publications

References 3 publications

A novel mutant Na⁺/HCO3⁻ cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

A novel mutant Na⁺/HCO3⁻ cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

Molecular Pathophysiology of Acid-Base Disorders

Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial?

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The Case | Renal tubular acidosis and eye findings

Cited by 20 publications

References 3 publications

A novel mutant Na+/HCO3− cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

A novel mutant Na+/HCO3− cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

Molecular Pathophysiology of Acid-Base Disorders

Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial?

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A novel mutant Na⁺/HCO3⁻ cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis

A novel mutant Na⁺/HCO3⁻ cotransporter NBCe1 in a case of compound‐heterozygous inheritance of proximal renal tubular acidosis