Hypertension Grand Rounds - Gitelman Syndrome

Gitelman Syndrome 

Mattias Roser, Nermin Eibl, Birgit Eisenhaber, Jasmin Seringer, Mato Nagel, Sylvia Nagorka, 

Friedrich C. Luft, Ulrich Frei and Maik Gollasch 

Hypertension. 2009;53:893-897; originally published online April 6, 2009; 

doi: 10.1161/HYPERTENSIONAHA.108.127993 

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Hypertension Grand Rounds 

Gitelman Syndrome 

Mattias Roser, Nermin Eibl, Birgit Eisenhaber, Jasmin Seringer, Mato Nagel, Sylvia Nagorka, 

Friedrich C. Luft, Ulrich Frei, Maik Gollasch 

Gitelman syndrome (GS) is an autosomal-recessive renal 

tubular disorder characterized by hypokalemia, hypomagnesemia, 

hypocalciuria, metabolic alkalosis, secondary 

hyperreninemic aldosteronism, and low blood pressure. 1–3 GS 

patients are usually diagnosed relatively late, because malaise, 

low blood pressure, hypokalemia, hypocalciuria, and 

hypomagnesemia are difficult to categorize clinically. Inactivating 

mutations in the SLC12A3 gene encoding the 

thiazide-sensitive sodium chloride cotransporter (NCCT) 

cause GS. 2 The investigators used the criteria of Bettinelli et 

al4 to identify patients with GS. More than 100 SLC12A3 

mutations have been described. 3 Most are missense mutations 

substituting conserved amino acid residues within putative 

functional domains of NCCT, whereas nonsense, frameshift, 

and splice site defects and gene rearrangements are less 

frequent. GS is clinically variable (men are more severely 

affected than women), and the combination of mutations 

present in each allele may determine phenotype variability. 3 

A heterozygous carrier state for 30 different inactivating 

mutations in NCCT, as well as genes responsible for Bartter 

syndrome, is associated with reduced blood pressure risk of 

hypertension in the general population. 5 Approximately 80% 

of the mutation carriers had systolic blood pressure values 

below the mean of the entire 5124-subject cohort of the 

Framingham Heart Study. The mean blood pressure reduction 

in carriers averaged �6.3 mm Hg for the systolic and 

�3.4 mm Hg for the diastolic blood pressures, similar to 

values obtained with chronic thiazide treatment. There was a 

60% reduction in the risk of developing hypertension by age 

60 years. Thus, rare alleles that affect renal salt handling and 

blood pressure in the general population could account for a 

substantial fraction of blood pressure variation. 5 We encountered 

2 patients and then found others in our database who 

illustrate the importance of NCCT on blood pressure variability 

and, therefore, hypertension. 

The Patients 

A 29-year-old man presented with a 14-year history of 

generalized weakness, severe muscle cramps with tetany, 

dyspnea, and anxiety. He had visited emergency departments 

on earlier occasions and received potassium and/or magnesium 

infusions for hypokalemia and hypomagnesemia. His 

symptoms had progressed to the point that he could no longer 

drive a car or use public transport. The patient denied nausea, 

vomiting, diarrhea, heat intolerance, excessive perspiration, 

and changes in bowel habits. He ingested no laxatives or 

diuretics, nor did he abuse alcohol or street drugs. His other 

clinical symptoms included fatigue, heart palpitations, dizziness, 

nocturia, polydipsia, polyuria, and thirst. 

The blood pressure was 100/60 mm Hg, and heart rate was 

90 bpm. There were no neurological findings or proximal 

muscle weaknesses. Imaging studies were unremarkable, as 

was the ECG. Laboratory tests showed hypokalemia 

(3.0 mmol/L) and hypomagnesemia (0.69 mmol/L), whereas 

serum calcium, sodium, and chloride levels were normal. The 

creatinine clearance was 134 mL/min per 1.73 m 2 . Urinary 

calcium excretion (1.0 mmol/24 hours) was decreased, 

whereas the urinary potassium and magnesium excretion 

were elevated (106 mmol/24 hours and 6.82 mmol/24 hours) 

in the face of his low serum values. The plasma renin 

concentration was elevated (172 ng/mL) while supine and 

increased (302 ng/mL) with standing. The corresponding 

plasma aldosterone levels were normal to mildly increased 

(120 ng/mL supine and 217 ng/mL standing). The 24-hour 

urinary sodium excretion was 141, 176, and 350 mmol/24 

hours on 3 consecutive days on an ad libitum intake. Arterial 

blood gases were pH 7.49, PCO 2 41.6 mm Hg, and HCO 3 � 

31.6 mmol/L. 

The parents and an older brother were asymptomatic, 

whereas his younger brother had similar, albeit less severe, 

symptoms. We sequenced the exons and flanking regions of 

SLC12A3 after written informed consent was given and found 

3 mutations in exons 10, 13, and 16. The patient and his 

brother were compound heterozygous, having inherited 

Phe548Leu and Pro643Leu from their mother and Gly439Ser 

from their father (please see Table S1 in the online data 

supplement at http://hyper.ahajournals.org). The Phe548Leu 

mutation has not been reported earlier and is localized in a 

transmembrane region (Figure). The highly conserved phenylalanine 

is exchanged for a leucine (Figure S1). Gly439Ser 

Received December 15, 2008; first decision January 6, 2009; revision accepted March 17, 2009. 

From the Division of Nephrology and Intensive Care Medicine (M.R., N.E., J.S., U.F., M.G.), Department of Medicine, Charité Campus Virchow, 

Berlin, Germany; Experimental Therapeutics Centre and Bioinformatics Institute, Agency for Science, Technology and Research (B.E.), Singapore; 

Experimental and Clinical Research Center and HELIOS Klinikum-Berlin (F.C.L., M.G.), Berlin, Germany; and the Center for Nephrology and Metabolic 

Disorders (M.N., S.N.), Weißwasser, Germany. 

Correspondence to Maik Gollasch, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Nephrology/Intensive Care Medicine, Augustenburger 

Platz 1, D-13353 Berlin, Germany. E-mail maik.gollasch@charite.de 

(Hypertension. 2009;53:893-897.) 

© 2009 American Heart Association, Inc. 

Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.108.127993 


http://hyper.ahajournals.org/ 893 by guest on December 18, 2012

894 Hypertension June 2009 

Extracellular Space 

N 

Trp161Xaa 

c.104delCinsTT 

Phe548Leu 

c.1927delC 

Gly770Asp 

Cytoplasm Gly841Arg Gln1012Arg 

and Pro643Leu have been reported previously in heterozygous 

GS patients 6 but not in this allelic combination. 7 

Although Gly439Ser and Pro643Leu would be sufficient to 

account for the symptoms in our patient, the presence of 3 

mutations (Gly439Ser and Pro643Leu/Phe548Leu) is the 

possible reason that his symptoms were remarkably severe. 

The patient was given oral magnesium and potassium 

supplementation (18 and 84 mmol/d, respectively). His serum 

potassium and magnesium levels improved to low-normal 

values, and his clinical symptoms improved. Magnesium and 

potassium supplementations in combination with antialdosterone 

medications, prostaglandin inhibitors, or angiotensinconverting 

enzyme inhibitors have been advocated. 8–10 Aldosterone 

antagonists or epithelial sodium channel blockers can 

be considered if symptomatic hypokalemia is not corrected 

by MgCl 2 administration. 11 A potential concern of using these 

drugs in patients with GS is that the salt wasting might 

worsen, especially if dietary salt intake is reduced or when 

salt is lost from the body through a nonrenal mechanism. 

Even high doses of the epithelial sodium channel blocker 

amiloride may fail to curtail the excessive kaliuresis in 

patients with GS. 1 Low concentrations of these drugs in the 

lumen of the cortical collecting duct and modulation of the 

distal tubular potassium channel (renal outer medullary potassium 

channel) conductance could be responsible. 12 Amiloride 

is, as such, problematic, because it seems to increase 

aldosterone production accompanied by insufficient stimulation 

of plasma renin activity. The authors invoke a rise in 

serum potassium as an explanation. 13 

Spironolactone and angiotensin-converting enzyme inhibitors 

had been given empirically to our patient earlier by his 

family doctors. Both drugs were stopped after 1 month each 

because of dizziness, probably as result of low blood pressure 

episodes. Amiloride was also tried. However, the patient 

discontinued this medication because of unexplained neck 

pain. We tried a course of aliskiren 150 mg/d to inhibit 

angiotensin-mediated aldosterone release; however, the aldosterone 

values did not decrease, and the metabolic alkalosis 

did not improve. Currently, the patient can tolerate his 

symptoms, in part because he now has a greater understanding 

of his disease. 

A 21-year-old woman presented with blurred vision, 

cramps, tongue discomfort, and fatigue. At age 11 years, she 

observed that eating bananas made her feel better. She had 

never been brought to an emergency department, was physically 

active, and was employed. Her general practitioner was 

Ser987Arg 

C 

Figure. Domain architecture and positions 

of mutations in SLC12A3 detected in the 

present study. 

concerned about severe hypokalemia and hypomagnesemia. 

She denied nausea, vomiting, diarrhea, heat intolerance, 

excessive perspiration, and changes in bowel habits. She had 

no history of laxatives or diuretic abuse, nor did she abuse 

alcohol or street drugs. She denied nocturia, polydipsia, 

polyuria, and thirst. 

The blood pressure was 115/80 mm Hg; heart rate was 85 

bpm. The physical examination was normal. She had hypokalemia 

(2.8 mmol/L) and hypomagnesemia (0.48 mmol/L), 

whereas serum calcium, sodium, chloride, creatinine levels 

were normal. The creatinine clearance was 122 mL/min per 

1.73 m 2 . Urinary excretion of calcium (0.37 mmol/24 hours) 

was decreased, whereas urinary excretion of potassium and 

magnesium (67.00 and 2.83 mmol/24 hours, respectively) 

were elevated in the face of her serum values. The urinary 

24-hour excretion of sodium was 145 mmol with an ad 

libitum intake. She also had a compensated metabolic alkalosis 

(pH 7.46, PCO 2 44.8 mm Hg, and HCO 3 � 31.0 mmol/L). 

Her parents were clinically unremarkable, whereas her 19year-old 

brother described similar general weakness and 

muscle cramps, although less frequent. 

With her approval, we again sequenced the exons and 

flanking introns of SLC12A3 and found a mutation in exon 26 

(Gln1012Arg), as well as a deletion of exon 1, codon 35 

(c.104delCinsTT). Our patient is compound heterozygous, 

having inherited c.104delCinsTT from her mother and 

Gln1012Arg from her father (please see Table S1). 

Gln1012Arg is a novel missense mutation (Figure) that 

affects a sequence position at which the glutamine is conserved 

throughout all vertebrates (Table S1). Because 

SLC12A3 codes for 1021 amino acids, Gln1012Arg is located 

in close proximity to the C-terminal end of the protein 

sequence. This variant is located in the most distal part of the 

C-terminal SCL12A3 cytoplasmic domain known to date. 

Analysis of our clinically suspected GS patient databank 

revealed no other subjects with Gln1012Arg. However, we 

did find 6 additional new SLC12A3 gene mutations in other 

subjects (Gly841Arg, Ser987Arg, c.1927delC, Trp161Xaa, 

Gly770Asp, and IVS25�1G�T; Figure and Table S1). In 

these subjects, the referring nephrologists or geneticists had 

suspected GS on the basis of clinical examination and 

laboratory tests. Family histories and medical charts were 

reviewed and showed clinical features consistent with GS. 

We treated this patient with oral magnesium and potassium 

supplementation (2.8 and 40.0 mmol/d). In addition, her local 

nephrologists prescribed ramipril 2.5 mg/d. Serum potassium 



and magnesium levels reached low-normal values, and clinical 

symptoms improved significantly but did not resolve 

completely. Oral magnesium supplementation was, therefore, 

increased, and clinical symptoms improved. However, restoration 

of normal magnesium and potassium values was 

difficult and was accompanied by nausea and diarrhea. 

Magnesium aspartate was replaced with magnesium chloride, 

which was more tolerable. 

Discussion 

Nephrologists are generally confronted with hypertension. 

However, a thorough knowledge of hypotensive syndromes, 

particularly GS, is important not only for clinical reasons but 

also to understand the complex genetics of blood pressure 

regulation in the general population. During a routine nephrology 

ward rotation, we discovered novel SLC12A3 mutations 

in 2 symptomatic GS patients (Phe548Leu, 

Gln1012Arg, and c.104delCinsTT). These results caused us 

to work up our databank of “suspicious” hypokalemic hypomagnesemic 

patients, and, again, we were successful. We 

found 6 other new SLC12A3 gene mutations (Gly841Arg, 

Ser987Arg, c.1927delC, Trp161Xaa, Gly770Asp, and 

IVS25�1G�T). We elected to move genetic analysis from 

the research laboratory to the routine clinical arena for several 

reasons. First, a precise diagnosis permits a more exact, 

goal-directed clinical care. Second, we learned that our 

patients wanted desperately to know specifically what was 

wrong and what the relevance could be for their current and 

future families. Our patients did not raise concerns about fear 

of privacy violations, higher insurance premiums, or similar 

concerns. 

Decreased reabsorption of sodium at the NCCT and subsequent 

increased potassium losses via the renal outer medullary 

potassium channel, largely driven by secondary aldosteronism, 

explain the hypokalemia and reportedly increased 

salt appetite in GS patients. The hypocalciuria and hypermagnesuria 

are more difficult to understand. Nijenhuis et al 14 

argued that enhanced passive calcium transport in the proximal 

tubule, rather than active calcium transport in distal 

convolution, explains thiazide-induced hypocalciuria. Their 

micropuncture experiments in mice demonstrated increased 

reabsorption of sodium and calcium in the proximal tubule 

during chronic thiazide treatment, whereas calcium reabsorption 

in the distal convolution appeared unaffected. Furthermore, 

thiazide administration still induced hypocalciuria in 

transient receptor potential channel subfamily V, member 5 

gene-deleted mice, in which active distal calcium reabsorption 

was abolished because of inactivation of the epithelial 

calcium channel TRPV5. Next, Nijenhuis et al 14 found that 

thiazide upregulated the sodium/proton exchanger, responsible 

for the majority of sodium and, consequently, calcium 

reabsorption in the proximal tubule, whereas the expression 

of proteins involved in active calcium transport was unaltered. 

The authors then performed experiments addressing the 

time-dependent effect of a single thiazide dose and showed 

that the development of hypocalciuria paralleled a compensatory 

increase in sodium reabsorption secondary to an initial 

natriuresis. Finally, hypomagnesemia developed during 

chronic thiazide administration and in NCCT gene-deleted 

Roser et al Gitelman Syndrome 895 

mice, accompanied by downregulation of the epithelial magnesium 

channel transient receptor potential channel subfamily 

M, member 6. Transient receptor potential channel subfamily 

M member 6 downregulation could represent a general 

mechanism involved in the pathogenesis of hypomagnesemia 

accompanying NCCT inhibition or inactivation. 14 

Human studies have also been performed. Cheng et al 15 

investigated 8 GS patients and 8 control subjects. Isotonic 

saline (3 L) over 3 hours was given. Baseline sodium 

excretion and creatinine clearance rates were similar in GS 

patients and controls, although calcium excretion rate was 

lower in GS patients. In GS patients, saline infusion caused a 

significantly greater sodium excretion rate than in controls, 

but there was only a small increase in the calcium excretion 

rate in both the first 6 hours and the subsequent 18 hours. The 

authors concluded that hypovolemia is not the sole cause of 

hypocalciuria in patients with GS. However, their clinical 

study had several deficits. Long-term sodium balance was not 

controlled in the subjects, and the GS patients likely had a 

reduced extracellular circulating volume under both control 

and expansion conditions compared with controls. 

Our patients illustrate the difficulties in managing GS. The 

tubular defect in GS itself cannot be corrected so that 

adequate supplementation of magnesium and potassium remains 

the cornerstone of treatment. However, restoration of 

normal magnesium and potassium values is difficult to 

achieve, because high doses of magnesium cause diarrhea. 

The bioavailability of magnesium preparations is variable. 

Magnesium oxide and magnesium sulfate have a significantly 

lower bioavailability compared with magnesium chloride, 

magnesium lactate, and magnesium aspartate. 11 We recommend 

administration of magnesium chloride orally to compensate 

for renal magnesium and chloride losses. Although 

antialdosterone therapy has been reported to increase plasma 

potassium and magnesium levels and to reduce the fractional 

excretion of potassium and magnesium in GS patients, 10 the 

role of inhibiting the renin-angiotensin-aldosterone system in 

GS patients is not clear. Estrogens seem to play a role because 

drospirenone, a novel progestogen developed for use as 

hormone therapy in postmenopausal women, in combination 

with 17�-estradiol, has a potassium-sparing effect that counteracts 

thiazide-induced potassium loss. 16 Future studies on 

NCCT-deficient mice might be helpful to understand the role 

of these systems in GS. NCCT-deficient mice on a mixed 

background have been shown to exhibit hypocalciuria and 

hypomagnesemia but no potassium and acid-base homeostasis 

disturbances. 17 NCCT-deficient mice backcrossed onto 

the C57BL/6 background showed mild compensated alkalosis 

with increased levels of plasma aldosterone 18 and an increased 

sensitivity to develop hypokalemia when exposed to 

reductions in dietary potassium. 19 These studies underscore 

the importance of the genetic background for the NCCTdeficient 

phenotype, which is also potentially relevant for 

understanding phenotypic variability and development of 

pharmacological treatments in GS. To date, there are no data 

about the effectiveness of renin and/or angiotensinconverting 

enzyme inhibition in GS available. Future studies 

on NCCT mice might help to clarify this issue. 



896 Hypertension June 2009 

Finally, we learned in the course of our study that mutations 

such as these have a distinct bearing on the complex 

genetics of hypertension in the general population. We could 

not conduct a study on GS prevalence. Our patient population 

is heterogeneous and generally of German, Turkish, or 

Middle Eastern background. The mutations reported here 

were all in German white subjects. Hsu et al 20 studied 500 

unrelated children from Taipei. They found 15 SLC12A3 

mutations in 10 of the children. In a 1852-subject Japanese 

study, GS mutations were encountered in 3.2% of subjects. 21 

The literature would suggest that GS is not rare and GS 

heterozygosity certainly not that uncommon. Knowledge of 

novel mutations might also be important for determining 

alleles with health benefits that are nonetheless under purifying 

selection and for defining the genetic architecture of 

hypertension. 5 In this respect, combined effects of rare 

independent mutations have been suggested to account for a 

substantial fraction of blood pressure variation in the population 

on the basis of analyzing the impact of the heterozygous 

carrier state for a limited number of inactivating 

mutations in the NCCT, sodium-potassium 2-chloride cotransporter, 

and renal outer medullary potassium channel. 22 

Recently, members of the Framingham Heart Study were 

screened for variation in 3 genes, namely, SLC12A3, 

SLC12A1, and KCNJ1. The investigators used comparative 

genomics, genetics, and biochemistry to identify subjects 

with mutations proven or inferred to be functional. These 

mutations were all heterozygous and rare but were found in 

�1% to 2% of the Framingham population. 5 They produced 

clinically significant blood pressure reductions and presumably 

protected the individuals from development of hypertension. 

These findings and the mutations we report here have 

implications for the genetic studies on hypertension and other 

common complex traits. Carriers of mutations causing GS 

compensate for renal salt wasting by increasing their salt 

intake, as shown in a large Amish kindred. 23 In agreement, we 

found that urinary 24-hour sodium excretion was high in the 

first patient probably because of increased salt appetite. 

However, the increased urinary sodium excretion in carriers 

of the mutations causing GS versus wild-type relatives was 

not reflected by significant blood pressure changes in adults 

of the above mentioned large Amish kindred with GS. 23 In 

contrast, another study showed that carriers of mutations 

causing GS had lower blood pressure values than controls, 

however, with similar urinary sodium excretion. 24 Notably, 

our second patient showed normal urinary 24-hour sodium 

excretion; however, she was a small, slight woman. For her 

size, her salt intake was generous. NCCT-deficient mice have 

no salt-losing phenotype on a regular diet, 17 and compensatory 

mechanisms for the loss of NCCT have been documented 

in various mouse models. 25 Finally, NCCT stands out 

as a target of with-no-lysine kinase (WNK) regulation, as 

discussed recently in a scholarly review. 26 The mirror image 

of GS is pseudohypoaldosteronism type II (PHAII), which is 

also called Gordon syndrome. PHAII features high blood 

pressure, hyperkalemia, and metabolic acidosis. All of the 

metabolic aberrancies in PHAII are corrected by thiazide 

diuretics, which recapitulate the features of GS. WNK4 and 

WNK1 mutations cause PHAII. WNK4 inhibits NCCT, an 

effect that is lost when WNK4 is mutated. WNK1 phosphorylates 

WNK4, which diminishes the WNK4 inhibition of 

NCCT. A gain-of-function WNK1 mutation causes PHAII. 

The WNKs also influence the renal outer medullary potassium 

channel and epithelial sodium channel. The findings that 

altered levels of WNK1 and WNK4 function influence blood 

pressure in humans are relevant because WNK4 lies only 1 

Mb from locus D17S1299, the site showing the strongest 

linkage to blood pressure variation in the Framingham Heart 

Study population. Variants that alter WNK function would of 

course also influence the GS phenotype in persons harboring 

NCCT mutations. 

Source of Funding 

This study was supported by the Deutsche Forschungsgemeinschaft. 

None. 

Disclosures 

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Online Supplement 

Gitelman syndrome 

Mattias Roser,* Nermin Eibl,* Birgit Eisenhaber, & Jasmin Seringer,* Mato Nagel, § Sylvia 

Nagorka, § Friedrich C. Luft, # Ulrich Frei,* Maik Gollasch* # 

*Department of Medicine, Division of Nephrology and Intensive Care Medicine, Charité 

Campus Virchow, 13353 Berlin, & Experimental Therapeutic Centre, Singapore 138669, 

# Experimental and Clinical Research Center and HELIOS Klinikum-Berlin, 13125 Berlin, and 

§ Center for Nephrology and Metabolic Disorders, 02943 Weißwasser, Germany 

Short title: Gitelman Syndrome 

Correspondence and offprint requests to: 

Maik Gollasch, MD, PhD 

Charité - Universitätsmedizin Berlin 

Campus Virchow-Klinikum, Nephrology / Intensive Care Medicine 

Augustenburger Platz 1 

D-13353 Berlin, Germany 

Phone: (+49) 30 450 653263 

Fax: (+49) 30 450 553909 

maik.gollasch@charite.de 



Supplementary Material Table S1. Patients with GS mutations. 

Patient DNA Sequence 

Mutation 

Deduced 

Protein 

Modification 

Homozygous Reference 

1 NM_001126108.1:c.1315G>A p.Gly439Ser - Mastroianni, 

Am J Gen 

1996 

NM_001126108.1:c.1644C>G p.Phe548Leu - Present 

study * 

NM_001126108.1:c.1928C>T p.Pro643Leu - Cruz, 

Kidney 

2001 

Int 

2 NM_001126108.1:c.104delCinsTT p.Ala35fs - Present 

study † 

NM_001126108.1:c.3035A>G p.Gln1012Arg - Present 

study * 

3 ‡ NM_001126108.1:c.482G>A p.Trp161X - Present 

study § 

NM_001126108.1:c.2549T>C p.Leu850Pro - Simon, Nat 

Gen 1996 

4 NM_001126108.1:c.2221G>A p.Gly741Arg - Simon, Nat 

Gen 1996 

NM_001126108.1:c.1927delC p.Pro643fs - Present 

study || 


http://hyper.ahajournals.org/ by guest on December 18, 2012 

3

5 ‡ NM_001126108.1:c.2309G>A p.Gly770Asp - Present 

study * 

NM_001126108.1:c.2953+1G>T 

(IVS25+1G>T ) 

- Present 

study 

6 NM_001126108.1:c.2521G>C p.Gly841Arg + Present 

study * 


Am J Gen 

1996 

NM_001126108.1:c.2961C>G p.Ser987Arg - Present 

study * 

The following mutations have been described previously, but not in this allelic combination. 

Patient DNA Sequence Mutation Deduced 

Protein 

Modification 

Homozygous Reference 


Am J Gen 

1996 

NM_001126108.1:c.2660G>A p.Arg887Gln - Kurschat, 

DMW 2003 

9 NM_001126108.1:c.1049C>T p.Ser350Leu + Riveira- 

Munoz, 



4

JASN 2007, 

heterozygote 

10 NM_001126108.1:c.941C>T p.Ser314Phe - Reissinger, 

Kidney 

Blood Press 

Res 2002 

NM_001126108.1:c.2954G>A p.Cys985Tyr - Syren, Hum 

Mutat 2002 

11 NM_001126108.1:c.1964G>A p.Arg655His - Simon, Nat 

Gen 1996 

NM_001126108.1:c.2885+1G>T 

(IVS24+1G>T) 

- Simon, Nat 

Gen 1996 

All positions of the detected mutations are indicated with respect to SLC12A3 gene (GeneID: 

6559) isoform3 (NM_001126108.1), the respective protein sequence is S12A3_HUMAN 

(accession number P55017) which is 9 amino acids shorter in comparison to isoform1 

(NP_000330.2) due to the usage of an alternate in-frame splice site in the 3’ coding region. 

As a consequence, some of the identifiers of mutations (with a localization between sequence 

position 807 and the C-terminus) that originally have been annotated in agreement with the 

longer sequence version (isoform1) have been adapted to the Uniprot sequence version 

(isoform3). For example the mutation c.2521G>C (p.Gly841Arg) was originally annotated as 

c.2548G>C (p.Gly850Arg) for the longer sequence. 



5

* In all of these missense mutations, an amino acid that is strongly conserved at the respective 

sequence position within vertebrates (supplemental material, sequence alignment, figure S1) 

is substituted by another amino acid. 

† This insertion is predicted to be fatal. The normal sequence is 

103 GCTGCCTATGAC… 

35 -A--A--Y--D-… 

which is predicted to change to 

103 GTTTGCCTATGA… 

35 -V--C--L--X- 

containing TGA as a stop codon. 

‡U.S. American family 

§ The stop codon TAG is predicted to prematurely terminate protein translation in exon 3 at 

position 161. This will lead to a truncated transcript and protein product. 

|| As a result of a frameshift, the normal sequence. 

1921 TACCGC CCC CAGTGC… 

641 -Y--R- -P- -Q--C-… 

is predicted to change to 

1921 TACCGC CCC AGT GCC… 

641 -Y--R- -P- -S- -A-… 

Since exon 16 starts with proline, at least this exon will be affected. 

Turkish families. 



6

Page 1 of 3 

Supplemental Figure S1: Multiple sequence alignment of SLC12A3 proteins 

. . : **:*:* * *:.*:*: *. : **:* :* : : . ** ****.:***:* 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN MAELPTTETPGDATLCSGRFTISTLLSSDEPSPPAAYDSSHPSHLTHSSTFCMRT----FGYNTIDVVPTYEHYANSTQPGEPRKVRPTLADLHSFLKQEGRHLHALAFDSRPSHEMTDG-LVEGEAGTSSEKNPEEPVRFGWVKGVMIR 145 

Pt|gi|114662622|ref|XP_001138088.1| MAELTTTETPGDATLCSGRFTISTLLSSDEPSPPAAYDSSHPSHLTHSSTFCMRT----FGYNTIDVVPAYEHYANSTQPGEPRKVRPTLADLHSFLKQEGRHLHALAFDSRPSHEMTDG-LVEGEAGTSSEKNPEEPVRFGWVKGVMIR 145 

Pa|gi|197098766|ref|NP_001125490.1| MAELPTTETPGDATLCSGRFTISTLLSSDEPSPPAAYDSSHPSHLTHGSTFCMRT----FGYNTIDVVPAYEHYANSTQPGEPRKVRPTLADLHSFLK-EGRHLHALALDSRPSHEMTDG-LVEDEAGTSSEKNPEEPVRFGWVKGVMIR 144 

Ma|gi|109128597|ref|XP_001093467.1| MAELPSTETPGDATLCSGRFTISTLLSSDEPSPPAACDSSHPSHLTHGSTFCMRT----FGYNTIDVVPAYEHYANSTQPGEPRKVRPTLADLHSFLKQEGRHLHALAFDSRPSHEMTDG-LVEDEAGTSSEKNPEEPVRFGWVKGVMIR 145 

Ec|gi|194208620|ref|XP_001493476.2| MAELPVSETPGDPALCSGRFTISTLLGGDEPPQPAAYDSSHPSHLTHGSTFYMRT----FGYNTIDVVPAYEHYANSALPGEPRKVRPTLADLHSFLKQEGSHLHALAFDSRPGHEMTDG-LVEDEAGTGGEKSPAEPVRFGWVKGVMIR 145 

Bt|gi|119910063|ref|XP_871112.2| MAELPVSEAPRDPALCSGRFTISTLLGGEEPPPPAAYDSSHPSHLTHGNTFYNRT----FGYNTIDVVPAYEHYANSALPGEPRKVRPTLADLHSFLKQEGSHLHALAFDSRPSHEMTDG-LVEDEAGINGEKNPEEPVRFGWVKGVMIR 145 

Cf|gi|73950363|ref|XP_535292.2| MAELPVSEMPGDPALCSGRFIISTLLGGDEPPPPAACDSSHPSHLTHGSTFYMRT----FGYNTIDVVPAYEHYANSALPGEPRKVRPTLADLHSFLKQEGSHLHALAFDTRPSHEMTDG-LVEDEAGTNSEKQPGEPVRFGWVKGVMIR 145 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE MAELPVTELPGD-ALCSGRFTISTLMGGDEP-PPAACDSSQPSHLTHGSTLYMRT----FGYNTIDVVPAYEHYANSALPGEPRKVRPTLADLHSFLKQEGSHLHALAFDGRQGRELTDG-LVEDETGTNSEKSPGEPVRFGWVKGVMIR 143 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT MAELPVTEMPGD-ALCSGRFTISTLLGGDEP-PPAACDNSQPSHLTHGSTLYLRT----FGYNTIDVVPAYEHYANSALPGEPRKVRPTLADLHSFLKQEGSHLHALAFDGRPGHELTDG-LVEDETGANSEKSPGEPVRFGWVKGVMIR 143 

Oc|gi|130505142|ref|NP_001076118.1| MAELPASETPGDPALCSGRFTISTLLVGDEPPPSAAYDGSHASHVTLGSSLYMRT----FGYNTIDVVPAYEHYANSTLPGEPRKLRPTLADLHSFLK-EGSPLHVLALDSRPSHEMTDG-LVEDEAGAGGEK-PGEPVRFGWVKGVMIR 143 

Gg|gi|118096212|ref|XP_414059.2| -MEVPFLQEAAG---CEG-----TQLS--------------------GSSLCTRT----FGYNTVDVVPAYEHYANSRGVGEAGRGRPSLADLHSILKPDPGHLRVPLPDPQRSNGLPD---AEEGAGEPSSAPAAEPVRFGWVKGVMIR 114 

Ss|gi|76445912|gb|ABA42822.1| --MEEVPAAPNEGISLSALRSQFSVNGEEGPKYGFDGNRYH--YGDGTSVASQNSTQILTGYDTLDVGPNYDFYANTNAQGRVRRSRPSLFQLHSNIEEDSCPPPLYEETNTGRAPG----DSSEEDVE---EPQSEPTRFGWVKGVMVR 139 

Om|gi|76445922|gb|ABA42831.1| --MEEVPAAPNEGISLSALRSQFSVNGEEGPKYGFDGSRYH--YGDGTSVASQNSSQILTGYDTLDVGPNYDFYANTNALGRVRRSRPSLFQLHSNIEEDSCPPPLYEETNTGRAPG----DSSEDDVE---EPQSEPTRFGWVKGVMIR 139 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM ---MELPGDGVHLASYGPRAPQLAVNG-KAPAGGLDGSGYYQCYRDGSSVASRGS-DAPTGYDTVDAPPHYDFYANTEVWGRRRRVRPSLYQLSVDPEQDDFKPPMYEETAGERMGGG---DSSEEEEEEHKEPPPEPPRFGWVQGVMIR 142 

DR|gi|113682309|ref|NP_001038545.1| ----------MNLQSARSPFSVSSLSNGDDRKFSLGGCSSY----DTDSVASRSS-GVFSGYDTLDAPPSYDFYTNTEVFGRAKKSRPSLFELHSNPQDDPSPPPLYEESSVD--------KQSPEDEDEPTEPPPEPARFGWAQGVMIR 127 

Aa|gi|84619346|emb|CAD92102.1| -MADVPPIETVKMTSFNKQLKVPPAGSDESYARYLYDNSKDGTYHSNGEANSQSS-APFSGYDTLDEAPNYDFYANTVVRGKVRKSRPSLFQLQSVLEEDSSPPPLYEEANRAAHGGINGEDSSEDEGE--MEPEVEPTRFGWVQGVMIR 146 

1.......10........20........30........40........50........60........70........80........90.......100.......110.......120.......130.......140.......150 

*********************** ***:**::* :* ***** ***:***:**.*************:*********:*****.************ *:.* :** *****:**::** **.**:******:***::**:**:: 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGAPIVDPINDIRIIGVVSVTVLLAISLAGMEWESKAQVLFFLVIMV 295 

Pt|gi|114662622|ref|XP_001138088.1| CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGAPIVDPINDIRIIGVVSVTVLLAISLAGMEWESKAQVLFFLVIMV 295 

Pa|gi|197098766|ref|NP_001125490.1| CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGAPIVDPINDIRIIGVVSVTVLLAISLAGMEWESKAQVLFFLVIMV 294 

Ma|gi|109128597|ref|XP_001093467.1| CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGAPIVDPINDIRIIGVVSVTVLLAISLAGMEWESKAQVLFFLVIMV 295 

Ec|gi|194208620|ref|XP_001493476.2| CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLIQEHGAPIVDPINDIRIIGVVTVTVLLGISLAGMEWESKAQVLFFLVIMV 295 

Bt|gi|119910063|ref|XP_871112.2| CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGSPIVDPTNDIRIIGVVTVTVLLAISLAGMEWESKAQVLFFLVIMV 295 

Cf|gi|73950363|ref|XP_535292.2| CMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGRVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEHGTPIVDPINDIRIIGVVTVTVLLAISLAGMEWESKAQVLFFLVIMV 295 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE CMLNIWGVILYLRLPWITAQAGIVLTWLIILLSVMVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGTPIVDPINDIRIIGVVTVTVLLAISLAGMEWESKAQVLFFLVIMV 293 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT CMLNIWGVILYLRLPWITAQAGIVLTWLIILLSVMVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQENGTPIVDPINDIRIIGVVTVTVLLAISLAGMEWESKAQVLFFLVIMV 293 

Oc|gi|130505142|ref|NP_001076118.1| CMLNIWGVILYLRLPWITAQAGIVLTWVIILLSVLVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFSFANAVGVAMHTVGFAETVRDLLQEYGTPIVDPINDIRIIGVVTVTVLLAISLAGMEWESKAQVLFFLVIMV 293 

Gg|gi|118096212|ref|XP_414059.2| CMLNIWGVILYLRLPWITAQAGIALTWLIILMSVTVTTITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVAVAMHTVGFAETVRDLLQEHNSLIVDPTNDIRIIGVLTVTVLLGISLAGMEWEAKAQILFFLVILV 264 

Ss|gi|76445912|gb|ABA42822.1| 

Om|gi|76445922|gb|ABA42831.1| 

CMLNIWGVILYLRLPWITAQAGIGLTWVIILLSSCITGITGLSTSAIATNGRVKGGGTYFLISRSLGPKLGGSIGLIFAFANAVAVAMHTVGFAETVQALMEESGASIVDPINDIRIIGVITVTCLLAISLAGMEWEAKAQVLFFFVILV 289 

CMLNIWGVILYLRLPWITAQAGIGLTWVIILLSSCITGITGLSTSAIATNGRVKGGGTYFLISRSLGPELGGSIGLIFAFANAVAVAMHTVGFAETVQALMQESGASIVDPINDIRIIGVITVTCLLAISLAGMEWEAKAQVLFFIVILV 289 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM CMLNIWGVILYLRLPWITAQAGIGLTWVIILLSSFITGITGLSTSAIATNGKVKGGGTYFLISRSLGPELGGSIGLIFAFANAVAVAMHTVGFAETVTDLMRENGVVMVDPINDIRIVGVITVTCLLGISMAGMEWESKAQVLFFLVIMV 292 

DR|gi|113682309|ref|NP_001038545.1| CMLNIWGVILYLRLPWITAQAGIGLTWIIILVSSSITGITGLSTSAIATNGKVKGGGTYFLISRSLGPELGGSIGLIFAFANAVAVAMHTVGFAETVQVLMQETEVSMVDKLNDIRIIGVITVTCLLAISMAGMEWESKAQVLFFFVIMI 277 

Aa|gi|84619346|emb|CAD92102.1| CMLNIWGVILYLRLPWITAQAGIGLTWVIIILSSCITGITGLSTSAIATNGKVKGGGTYFLISRSLGPELGGSIGLIFAFANAVAVAMHTVGFAETVQSLMQESGASMVDPINDIRIIGVITVTCLLGISLAGMEWESKAQVIFFLVIMI 296 

.......160.......170.......180.......190.......200.......210.......220.......230.......240.......250.......260.......270.......280.......290.......300 

** .*: **:**.: :* ::**:** :.:**. *:** *** :*.***:*********************:** :***:**::******:*** :::**.:*::***** :**:: * *:.* * *:*:.* . 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN SFANYLVGTLIPPSEDKASKGFFSY---------RADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANISGDLKDPAIAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGVLNDTVTPGW--GACEGLACSYGWNFTECTQQH 434 

Pt|gi|114662622|ref|XP_001138088.1| SFANYLVGTLIPPSEDKASKGFFSY---------RADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANISGDLKDPAIAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGVLNDTVTPGW--GACEGLACSYGWNFTECTQQQ 434 

Pa|gi|197098766|ref|NP_001125490.1| SFANYLAGTLIPPSEDKASKGFFSY---------RADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANISGDLKDPAIAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGVLNDTVTPGW--GACEGLACSYGWNFTECTQQH 433 

Ma|gi|109128597|ref|XP_001093467.1| SFANYLVGTLIPPSEDKASKGFFSY---------RADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANISGDLKDPAVAIPKGTLMAIFWTTISYLAISATIGSCMVRDASGVLNDTVTPGW--GACEGLACGYGWNFTECTQQH 434 

Ec|gi|194208620|ref|XP_001493476.2| SFANYLVGTLIPPSEDKASKGFFSY---------RGDIFVQNLVPDWRGVDGSFFGMFSIFFPSATGILAGANISGDLRDPAVAIPKGTLMAIFWTTVSYLAISATIGSCVVRDASGDLNDTMTPGS--GACEGLACGYGWNFTHCSQQH 434 

Bt|gi|119910063|ref|XP_871112.2| SFANYLVGTLIPPSEEKASKGFFSY---------RADIFVQNLVPEWRGMDGSFFGMFSIFFPSATGILAGANISGDLKDPAVAIPKGTLMAIFWTTVSYLAISATIGSCVVRDASGGLNDTVTPGS--GACEGLACGYGWNFTECAQQR 434 

Cf|gi|73950363|ref|XP_535292.2| SFANYLVGTLIPPSEDKASKGFFSY---------RGDIFVQNLVPDWRGADGSFFGMFSIFFPSATGILAGANISGDLKDPAVAIPKGTLMAIFWTTVSYLAISATIGSCVVRDASGVLNDTVTAGS--GACEGLACGYGWNFTECAHQG 434 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE SFANYLVGTLIPASEDKASKGFYSY---------HGDIFVQNLVPDWRGIDGSFFGMFSIFFPSATGILAGANISGDLKDPAVAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGDVNDTMTPGP--GPCEGLACGYGWNFTECSQQR 432 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT SFANYLVGTLIPASKDKASKGFYSY---------HGDIFVQNLVPDWRGIDGSFFGMFSIFFPSATGILAGANISGDLKDPAVAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGDVNDTITPGP--GLCEGLACGYGWNFTECSQQH 432 

Oc|gi|130505142|ref|NP_001076118.1| SFTNYLVGTLIPPSEDKASKGFFSY---------RGDIFVQNLVPDWRGVDGSFFGMFSIFFPSATGILAGANISGDLKDPAVAIPKGTLMAIFWTTVSYLAISATIGACVVRDASGNLNDTVTPGL--GACEGLACGYGWNFTECAQRH 432 

Gg|gi|118096212|ref|XP_414059.2| SFINYLVGTVIPASAEKQAKGFFSY---------RADIFAQNFVPDWRGPEGSFFGLFSIFFPSATGILAGANISGDLKDPALAIPKGTLMAIFWTTVSYLVLSATIGACVLRDASGSLNDSVAVGS--PGCEGLGCSYGWNFTDCAQRQ 403 

Ss|gi|76445912|gb|ABA42822.1| SFANYIVGTIIPATPQKQAKGFFSY---------QADIFAENFVPGWRGPEGNFFGMFSIFFPSATGILAGANISGDLKDPTVAIPRGTLMAIFWTTLSYLIIAATIGACMVRDASGIMNDTLVMSS-ADSCQGLACQYGWDFTNCITNR 429 

Om|gi|76445922|gb|ABA42831.1| SFANYIVGTIIPATPQKQAKGFFSYQGQSSMAFRQSDIFAENFVPNWRGPEGNFFGMFSIFFPSATGILAGANISGDLKDPTVAIPRGTLMAIFWTTLSYLIIAATIGACLVRDASGIMNDTLAMSS-ADSCQGLACQYGWDFTDCITNR 438 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM SFVNYIVGTIIPASPQKQAKGFFSY---------KAEIFAANFVPGWRGKEGSFFGMFSIFFPSATGILAGANISGDLKDPTVAIPRGTLMAIFWTTISYLIISATIGACVVRDASGELNDTLSYSSSSENCSGLACQYRWDFSECIKNN 433 

DR|gi|113682309|ref|NP_001038545.1| SFASYIIGTIIPATPQKQARGFFSY---------RADIFATNFVPGWRGPEGSFFGMFSIFFPSATGILAGANISGDLKDPNVAIPRGTMLAIFWTTVSYLIISATIGSCVVRDASGDVNDTISSLT--GECLGVGCNYGWNFTDCMTNN 416 

Aa|gi|84619346|emb|CAD92102.1| SFVNYFVGTVIPATPQKQARGFFSY---------RADIFAANFVPQWRGPDGSFFGMFSIFFPSATGILAGANISGDLRDPAVAIPRGTLMAIFWTTMSYLLISSTIASCVLRDASGSMNDSVPISD-TGNCVGLGCRYGWDFSECTNNK 436 

.......310.......320.......330.......340.......350.......360.......370.......380.......390.......400.......410.......420.......430.......440.......450 

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Roser M. et al.: Multiple sequence alignment of SLC12A3 proteins 

:* .*: * **:**:**...***:******************.******* *.*** **:*.** *** **:*.*:*:: **: *::*****:************************:********:*::*.** :*:*: .::***** 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN SCHYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCEDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISVVIMFLL 584 

Pt|gi|114662622|ref|XP_001138088.1| SCHYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCEDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISVVIMFLL 584 

Pa|gi|197098766|ref|NP_001125490.1| SCHYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCKDQLYPLIGFFGKGYGKNKEPVRGYLLAHAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISMVIMFLL 583 

Ma|gi|109128597|ref|XP_001093467.1| SCRYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCKDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIVIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISVVIMFLL 584 

Ec|gi|194208620|ref|XP_001493476.2| SCRYGLINYYQSMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCVDQLYPLIGFFGKGYGKNNEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWAALFGAVISVVIMFLL 584 

Bt|gi|119910063|ref|XP_871112.2| SCRYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCLDQLYPLIGFFGKGYGKNNEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWAALFGAIISVVIMFLL 584 

Cf|gi|73950363|ref|XP_535292.2| SCRYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCQDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWSALFGAVISVVIMFLL 584 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE SCRYGLINYYQTMSMVSAFAPLITAGIFGATLSSALACLVSAAKVFQCLCEDQLYPLIGFFGKGYGKNREPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWAALFGAVISVVIMFLL 582 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT SCRYGLINYYQTMSMVSAFAPLITAGIFGATLSSALACLVSAAKVFQCLCEDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWAALFGAVISVVIMFLL 582 

Oc|gi|130505142|ref|NP_001076118.1| SCRYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCEDQLYPLIGFFGKGYGKNNEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWSALFGAVVSVVIMFLL 582 

Gg|gi|118096212|ref|XP_414059.2| SCRYGLSNYYQSMSMVSGFGPLITAGIFGATLSSALACLVSAPKVFQCLCKDQLYPLIGFFGKGYGKNSEPIRGYMLTYAIAIGFILIAELNAIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWAALFGATISVVIMFLL 553 

Ss|gi|76445912|gb|ABA42822.1| TCTYGLSNQYQSMSLVSGFAPLITAGIFGATLSSALACLVSAPKVFQCLCKDNLYPVIGFFGKGNGKNDEPIRGYVLAYIIAVCFVLIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRFYSKWMSLLGAVVSVIIMFLL 579 

Om|gi|76445922|gb|ABA42831.1| TCTYGLSNQYQSMSLVSGFAPLITAGIFGATLSSALACLVSAPKVFQCLCKDNLYPVIGFFGKGNGKNDEPIRGYVLAYIIAVCFVLIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRFYSKWMSLLGAVVSVIIMFLL 588 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM TCKHGIMNYYQSMSLVSAFAPLISAGIFGATLSSALACLVSAPKVFQCLCKDQLYPLIGFFGKGYGKNAEPLRAYLLTYVIAVCFVLIAELNTIAPIISNFFLCSYALINFSCFHASVTNSPGWRPSFRFYSKWLSLLGAVCCVVIMFLL 583 

DR|gi|113682309|ref|NP_001038545.1| TCTYGLSNYYQSMSMVSAVAPLITAGIFGATLSSALACLVSAPKVFQCLCKDKLYPGIGFFGKGYGKNNEPLRSYLLAYIIAICFILIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPTFRFYSKWLSLLGAVVSVIIMFLL 566 

Aa|gi|84619346|emb|CAD92102.1| TCAFGISNYYQSMSMVSGFAPLIAAGIFGATLSSALACLVSAPKVFQCLCKDRLYPFIGIFAKGYGKNDEPIRGYVLTYVIAICFILIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFRYYSKWLSLLGSVVSVIIMFLL 586 

.......460.......470.......480.......490.......500.......510.......520.......530.......540.......550.......560.......570.......580.......590.......600 

********:*:::*** *.:**:* ******:**.**. **. ...*. *::*:**********:*** **:***::. :*:. ***:*.:*: . . :. * ** :*::::** * * *** **: *::.:***::: 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLIGPHKQRMPELQLIANGHTKWLNKRKIKAFYSDVIAEDLRRGVQILMQAAGLGRMK 734 

Pt|gi|114662622|ref|XP_001138088.1| TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLIGPHKQRMPELQLIANGHTKWLNKRKIKAFYSDVIAEDLRRGVQILMKAAGLGRMK 734 

Pa|gi|197098766|ref|NP_001125490.1| TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSAGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLIGPHKQRMPELQLIANGHTKWLKKRKIKAFYSDVIAEDLRRGVQILMQAAGLGRMK 733 

Ma|gi|109128597|ref|XP_001093467.1| TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLIGPHKQRMPELQLIASGHTKWLNKRKIKAFYSDVIAEDLRKGVQILMQASGLGRMK 734 

Ec|gi|194208620|ref|XP_001493476.2| TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSSSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLVGPRKQRMPELRLIANGHTKWLNKRKIKAFYSDVIAEDLRSGVQILMQAAGLGRMK 734 

Bt|gi|119910063|ref|XP_871112.2| TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLMGPRKQRMPELRLIANGHTKWLNKRKIKAFYSDVLAEDLRSGVQVLMQAAGLGRMK 734 

Cf|gi|73950363|ref|XP_535292.2| TWWAALIAIGVVLFLLLYVIYKKPDVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLIGPRKQRMPELRLIANGHTKWLNKRKIKAFYSDVIAEDLRSGVQILMQAAGLGRMK 734 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVSTFTQNLSLMICGHVLIGPGKQRVPELRLIASGHTKWLNKRKIKAFYSDVIAEDLRSGVQILMQASGLGRMK 732 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT TWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVSTFTQNLSLMICGHVLIAPGKQRVPELRLIASGHTKWLNKRKIKAFYSDVIAEDLRSGVQILMQASGLGRMK 732 

Oc|gi|130505142|ref|NP_001076118.1| TWWAALIAIGVILFLLLYVIYKKPEVNWGSSVQAGSYNLALSYAVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTQNLSLMICGHVLIGPRKQRMPELRLIASGHTKWLNKRKIKAFYSDVAAEDLRSGVQSLMQASGLGRMK 732 

Gg|gi|118096212|ref|XP_414059.2| TWWAALIALGIVIFLLGYVLYKKPDVNWGSSMQASSYNLALSYSVGLSEVDEHIKNYRPQCLVLTGPPNFRPALVDFVGTFTKNLSLMICGNVLIGPSKQKVLEARQASDGHTRWLLKRKIKAFYTNVLAEDLRSGVQMLLQAAGLGKMR 703 

Ss|gi|76445912|gb|ABA42822.1| TWWAALIAIGIVIFLLGYVLYKRPTVNWGSSVQAGSYNMALSYCVSLNQVDDHIKNYRPQCLVLTGPPSCRPALVDFVGTFTKNLSLMICGNVVTG-GPSPATLDTASSNSHVTWLNKRQIKSFYHGVVANDLRTGVKMLLQGAGLGRIR 728 

Om|gi|76445922|gb|ABA42831.1| TWWAALIAIGIVIFLLGYVLYKRPSVNWGSSVQAGSYNMALSYCVSLNQVDDHIKNYRPQCLVLTGPPSCRPALVDFVGTFTKNLSLMICGNVVTG-GPSPATLDTASSNSHVTWLNKRQIKSFYHGVVANDLRTGVKMLLQGAGLGRIR 737 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM TWWAALIAFGVVFFLLGYTLYKKPAVNWGSSVQASSYSMALNQCVGLNQVEDHVKNYRPQCLVLTGPPCCRPALVDLVGCLTKRLSLMMCGHVVTA-GPSP------VSERHVTWLNQRKVRSFYRGVVAADLRSGVNMLLQGAGLGRIK 726 

DR|gi|113682309|ref|NP_001038545.1| TWWAALIAIGIVIFLLGYVLYKKPEVNWGSSMQASSYNMALSQCVGLNQVEDHIKNYRPQCLVLSGPPCARPSLVDFIGAFTKNQSLMICANVLAS-GPSPGTADS-MSSTHLKWLNNRKIKSFYHTVVADDLRTGVQMLLQSTGLGRMK 714 

Aa|gi|84619346|emb|CAD92102.1| TWWAALIAIGIVLFLLGYVLYKKPSVNWGSSVQASSYNTALSHSVSLNYVDDHIKNYRPQCLVLTGPPSLRPALVDFVSTFTKNLSLMICGNVVVA-GPSPAATESAGSSSHVAWLNKRHVRSFYRGVVADDLRGGVQMLLQASGLGRMK 735 

.......610.......620.......630.......640.......650.......660.......670.......680.......690.......700.......710.......720.......730.......740.......750 

**:: *:*::* * ..*:*:*****:: :***::*::***: . * : . *.:: ** .****:**:*** **** * *** :::**. * :******: :: : 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN PNILVVGFKKNWQSAHPATVEDYIGILHDAFEFNYGVCVMRMREGLNVSKMMQAHINPVFDPAEDGKEASAR-----------VDPKALVKEEQATTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLGRKRRWSKCKIRVFVGGQINRMD 873 

Pt|gi|114662622|ref|XP_001138088.1| PNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGLNVSKMMQAHINPVFDPAEDGKEASAR-----------VDPKALVKEEQATTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLGRKKRWSKCKIRVFVGGQINRMD 873 

Pa|gi|197098766|ref|NP_001125490.1| PNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGLNVSKMMQVHINPVFDPAEDAKEASAR-----------VDPKALVQEEQATTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLGRKKRWSKCKIRVFVGGQINRMD 872 

Ma|gi|109128597|ref|XP_001093467.1| PNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGLNVSKMMQAHINPVFDPAEDGKEASAR-----------VDPKALVQEEQATTVFQSEQGKKTIDIYWLFDDGGHTN-KPYLTEHHKRWSKCKIRVFVGGQINRMD 872 

Ec|gi|194208620|ref|XP_001493476.2| PNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGLNISEMMQAHINPVFDPAEDRKEAIAR-----------VDPEALVREEQASTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLGRKKRWSKCAIRVFVGGQINRMD 873 

Bt|gi|119910063|ref|XP_871112.2| PNILVIGFKKNWQSAHPATVEDYIGILHDAFDLNYGVCVMRMREGLNISEVMQAHINPMFDPAEDSKEARAGGA--HLSVSGTVDPEALVQEEQASTVFQSEQGKKTIDIYWLFDDGGLTLLIPYLLGRKKRWSKCRIRVFVGGQINRMD 882 

Cf|gi|73950363|ref|XP_535292.2| PNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGLNISEVMQAHINPVFDPAEDSKEASTNGA--RPSVSGTLDPDALVREEQASTIFQSEQGKKSIDIYWLFDDGGLTLLIPYLLGRKKRWSKCKIRVFVGGQINRMD 882 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE PNILVVGFKRNWQSAHPATVEDYIGVLHDAFDFNYGVCVMRMREGLNVSEALQTHT----------------------------TPEALIQEEQASTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLHRKKRWGKCKIRVFVGGQINRMD 854 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT PNILVVGFKKNWQSAHPATLEDYIGILHDAFDFNYGVCIMRMREGLNVSEALQTHT----------------------------APEALVQEEQTSTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLHRKKRWGKCKIRVFVGGQINRMD 854 

Oc|gi|130505142|ref|NP_001076118.1| PNILVVGFKKNWQAAHPATVEDYIGILHDAFDLSYGVCVMRMREGLNVSEVMQAHINPTFDPAEDGKAASTGGA--RPAVSGAAEPETLAREEQASTVFQLEQGKKTIDIYWLFDDGGLTLLIPYLLGRKKRWSRCKIRVFVGGQINRMD 880 

Gg|gi|118096212|ref|XP_414059.2| PNIVTLGYKRDWQAAAPQSLEDYVGILHDAFDFKHGVCLLRLREGLNVSRVPQAHINPAFGAAEHPDGNGAGG--------RAAPSTSIDPEQQASTIFQSQQGKKTIDIYWLFDDGGLTLLIPYLLGRKKRWGKCKVRVFVGGQINRMD 845 

Ss|gi|76445912|gb|ABA42822.1| PNVLLTGFKRDWRKDKPSCIDNYIGILHDAFDLQYGVCVLRMREGLDMFRQAQTHVNPGFESSPERGVNTCVPPAPPANFSLDPDSMVTEPQPQPSTVFQSQQGKKTIDVYWLFDDGGLTLLLPYLLTRKKRWARCKVRVFVGGDIQRKE 878 

Om|gi|76445922|gb|ABA42831.1| PNVLLTGFKRDWRKDKPSCIDNYIGILHDAFDLQYGVCVLRMREGLDVFRQAQTHVNPGFEASPESGVNTCVPPAPPANFSLDPDAMVTEPQPQPSTVFQSQQGKKTIDVYWLFDDGGLTLLLPYLLTRKKRWARCKVRVFVGGDIQRKE 887 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM PNVLLMGFKKDWGCDSPQAAHHYIGILHDAFDLHYGVCVLRVKEGLDASHPPQCHVNPGFDGGPESINTVCAPACVQTSVTS---SVSMDPDPQPSSVFQKKQGKKTIDIYWLSDDGGLTLLLPYLLTRRKRWAGCKVRVFVGGDTDKKE 873 

DR|gi|113682309|ref|NP_001038545.1| PNVLVMGYKKNWRKVQPGIIENYVGILHDAFDLQYGVCVLRMKEGLDITRTIQAQVNLGFETSTEQGLDTNSTAPTSPTIEASLDPETLMALTQPSTLFQTRQGKKTIDVYWLSDDGGLTLLIPYLLTRKKRWGRCKVRVFVGGEAQQIE 864 

Aa|gi|84619346|emb|CAD92102.1| PNVLVMGYKQNWNQDRPHCVENYVGILHDAFDLQYGVCVLRMKEGLDVSHSLQAHVNPVYES----DIGLCPPPPLPANAILDPDALVAAP--QTSTGFQSKQGKKTIDVYWLSDDGGLTLMLPYLLSRKKRWARCKVRVFVGGERQRME 879 

.......760.......770.......780.......790.......800.......810.......820.......830.......840.......850.......860.......870.......880.......890.......900 



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Page 3 of 3 

Roser M. et al.: Multiple sequence alignment of SLC12A3 proteins 

:::: : *:.:*****:::.:**** *: . :*:: : :*:. * . : . .* :::::: : *: **:**.*:: **:**:: :*:*:**: ***.*::***: :*:** ***:*:********* *** 

Hs|gi|1717801|sp|P55017.1|S12A3_HUMAN QERKAIISLLSKFRLGFHEVHILPDINQNPRAEHTKRFEDMIAPFRLNDGFK--DEATVNEMRRDCPWKISDEEITKNRVKSLRQVRLNEIVLDYSRDAALIVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1021 

Pt|gi|114662622|ref|XP_001138088.1| QERKAIISLLSKFRLGFHEVHILPDINQNPRAEHIKRFEDMIAPFRLNDGFK--DEATVNEMRRDCPWKISDEEITKNRVKSLRQVRLNEILLDYSRDAALIVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1021 

Pa|gi|197098766|ref|NP_001125490.1| QERKAIISLLSKFRLGFHEVHILPDINQNPRAEHTKRFEDMIAPFRLNDGFK--DEATVNDMRRDCPWKISDEEITKNRVKSLRQVRLNEILLDYSRDAALIVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTVYCQ 1020 

Ma|gi|109128597|ref|XP_001093467.1| QQRKAIISLLSKFRLGFHEVHILPDINQNPRAERTKRFEDMIAPFRLNDGFK--DEATVNEMRRDCPWKISDEEMRKNRVKSLRQVRLNEILLDYSRDAALIVITLPIGRKGECPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1020 

Ec|gi|194208620|ref|XP_001493476.2| QERKAIISLLSKFRLGFHEVHVLPDINQKPRAEHTKRFEDMIAPFRLNDGFK--DEATVTEMRRDCPWKISDEEINKNRVKSLRQVRLNEILLDYSRDAALVVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1021 

Bt|gi|119910063|ref|XP_871112.2| QERKAIISLLSKFRLGFHEVHVLPDINQKPRAEHIKRFEDMIAPFRLNDGFK--DEATVTEMRRDCPWKISDEEINKNRIKSLRQVRLNEILLDYSRDAALVVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1030 

Cf|gi|73950363|ref|XP_535292.2| QERKAIISLLSKFRLGFHEVHVLPDINQKPRAEHTKRFEDMIAPFRLNDGFK--DEATVAEMRRDCPWKISDEEINKNRVKSLRQVRLNEILLDSSRDAALVVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1030 

Mm|gi|27151683|sp|P59158.1|S12A3_MOUSE EERKAIISLLSKFRLGFHEVHVLPDINQKPQAEHTKRFEDMIAPFRLNDGFK--DEATVTEMRRDCPWKISDEEINKNRIKSLRQVRLSEILLDYSRDAALIILTLPIGRKGKCPSSLYMAWLETLSQDLRPPVLLIRGNQENVLTFYCQ 1002 

Rn|gi|27151789|sp|P55018.2|S12A3_RAT EERKAIISLLSKFRLGFHEVHVLPDINQKPQVEHTKRFEDMIAPFRLNDGFK--DEATVAEMRRDYPWKISDEEINKNRIKSLRQVRLNEILLDYSRDAALIILTLPIGRKGKCPSSLYMAWLETLSQDLSPPVLLIRGNQENVLTFYCQ 1002 

Oc|gi|130505142|ref|NP_001076118.1| QERKAMVSLLSKFRLGFHEVHVLPDINQKPRAEHTKRFEDMIAPFRLNDGFK--DEATVAEMRRDCPWKISDEEINKNRIKSLRQVRLNEILLDYSRDAALVVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 1028 

Gg|gi|118096212|ref|XP_414059.2| EERKAIVSLLSKFRLGFHEVHILPDINQQPRPEHIRRFDELIAPFRLNDGFK--DEAAVNELRHGCPWKISDEEVHRHRAKSLRQVRLNEILLDYSRDAALIAITLPIGRKERCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ 993 

Ss|gi|76445912|gb|ABA42822.1| EQRKEVMDLISKFRLGFHDVEVLPDINARPQPEHVRRFEDLIGPYRLNTAQK-DGHVTAEQLNQDCPWMVSDEEIETNKPKTLRQIRLNEVLQDYSRDAAIIFVTMPVGRRGQCPSALYMAWLETLSRDLRPPVLLVRGNQENVLTFYCQ 1027 

Om|gi|76445922|gb|ABA42831.1| EQRKEVMDLISKFRLGFHDVEVLPDINARPQPEHVRRFEDLIGPYRINTAQK-DGHVTAEQLNQDCPWMVSDEEIETNKPKTLRQIRLNEVLQDYSRDAAIIFVTMPVGRRGQCPSALYMAWLETLSRDLRPPVLLVRGNQENVLTFYCQ 1036 

Ps|gi|1717802|sp|P55019.1|S12A3_PSEAM EQKEEVLALIKKFRLGFHDVEVLPDIHQPPQPGNVDHFEDSVNRFRLETNPKQDSDSGPQQQQQEEPWMITEQDLERNRAKSLRQIRLNEVLQVHSREAALIVITMPVGRRGVCPSTLFLAWLDVLSRDLRPPVLLVRGNQENVLTFYCQ 1023 

DR|gi|113682309|ref|NP_001038545.1| EQKKELKGLISRFRLGFKDIQVLPDINGAPQSEHIRKFEDFIAPYRVSSVQK-DGQE-ADEATKEFSWMVSDEEMETFKAKSLRQIRLNEVIQDYSRDAALIVVTMPVGRRGSCPSPLYMAWLEIVSRDLRPPVLLVRGNQENVLTQYCQ 1012 

Aa|gi|84619346|emb|CAD92102.1| EQKQEILALISKFRLGFHDVEVLPDIGGKPQTEHMKRFEDMLGPYRLNDGQK--DSSAVEQLREGCPWMISDEELERNKAKSQRQVRLNEILLDYSRDAALIVLTMPVGRRGGCPSTLYMAWLETLSRDLRPPVLLVRGNQENVLTLYCQ 1027 

.......910.......920.......930.......940.......950.......960.......970.......980.......990......1000......1010......1020......1030......1040......1050 



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Supplementary Material Figure S1: Multiple sequence alignment of SLC12A3 proteins 

The sequence identifier indicates the taxon (first two letters) followed by the protein 

accession numbers. The gray bars at the bottom represent the degree of amino acid type 

conservation of alignment positions. An asterisk at the top highlights completely 

conserved amino acids at the given alignment position. The alignment was generated 

with CLUSTALX 1 . Taxon abbreviations: Aa, Anguilla anguilla; Bt, Bos taurus; Cf, 

Canis familiaris; Dr, Danio rerio; Ec, Equus caballus; Gg, Gallus gallus; Hs, Homo 

sapiens; Ma, Macaca mulatta; Mm, Mus musculus; Oc, Oryctolagus cuniculus; Om, 

Oncorhynchus mykiss; Pa, Pongo abelii; Ps, Pseudopleuronectes americanus; Pt, Pan 

troglodytes; Rn, Rattus norvegicus; Ss, Salmo salar

Hypertension Grand Rounds - Gitelman Syndrome

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