Letter to the Editor
Novel nonsense mutation in the SLC12A3 gene in a Spanish case of Gitelman syndrome
Nueva mutación finalizadora en el gen SLC12A3 en un caso de síndrome de Gitelman en España
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The prevalence of GS is estimated to range around 25 cases per 1 million, making it one of the most frequent inherited renal tubular disorders.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A 35-year-old male, with a history of seborrheic dermatitis treated with topical steroids and iron deficiency anemia was admitted with a first episode of biliary colic and hypokalemia (2.9 mEq/L). His electrolyte imbalance, once the vomiting settled, was challenging to manage with oral potassium supplements.</p><p id="par0015" class="elsevierStylePara elsevierViewall">He complained of thirst, muscle weakness and fatigue with limited exertion. He had occasional and doubtful arthritis. At the time of the visit, the patient did not present any gastrointestinal symptoms, except reflux due to treatment with potassium, but that was well controlled with a gastric protector.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The exploration was normal but on his electrocardiogram (ECG) we found a prominent U wave. Blood tests showed normal renal function with serum creatinine 0.81<span class="elsevierStyleHsp" style=""></span>mg/dL, glomerular filtration rate (GFR) 116<span class="elsevierStyleHsp" style=""></span>mL/min per 1.73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>, potassium 2.9<span class="elsevierStyleHsp" style=""></span>mEq/L, sodium 141<span class="elsevierStyleHsp" style=""></span>mEq/L, chloride 98<span class="elsevierStyleHsp" style=""></span>mEq/L, phosphate 2.5<span class="elsevierStyleHsp" style=""></span>mg/dL, magnesium 1.57<span class="elsevierStyleHsp" style=""></span>mg/dL, calcium 9.6<span class="elsevierStyleHsp" style=""></span>mg/dL, mild elevation of white blood cell (WBC) count of 10,640 per mm<span class="elsevierStyleSup">3</span> (normal range 3500–10,500 per mm<span class="elsevierStyleSup">3</span>), hemoglobin 15.2<span class="elsevierStyleHsp" style=""></span>g/dL, liver function was normal, plasma renin activity 1.56<span class="elsevierStyleHsp" style=""></span>ng/mL/h with normosodic diet and supine position (normal range 0.2–2.8<span class="elsevierStyleHsp" style=""></span>ng/mL/h), metabolic alkalosis with pH 7.50 and bicarbonate 30.4<span class="elsevierStyleHsp" style=""></span>mmol/L, urinary sediment with mild density of 1008<span class="elsevierStyleHsp" style=""></span>g/L and pH 8, excretion in 24-h urine collection (4200 mm<span class="elsevierStyleSup">3</span>) 48<span class="elsevierStyleHsp" style=""></span>h without supplementation and diet of salt 5 grams showed glucose 105<span class="elsevierStyleHsp" style=""></span>mg, uric acid 1210<span class="elsevierStyleHsp" style=""></span>mg, creatinine 1617<span class="elsevierStyleHsp" style=""></span>mg, potassium 232<span class="elsevierStyleHsp" style=""></span>mEq, sodium 512<span class="elsevierStyleHsp" style=""></span>mEq, chloride 326<span class="elsevierStyleHsp" style=""></span>mEq, phosphate 1427<span class="elsevierStyleHsp" style=""></span>mg, magnesium 227<span class="elsevierStyleHsp" style=""></span>mg, calcium 81<span class="elsevierStyleHsp" style=""></span>mg, protein excretion 0.15<span class="elsevierStyleHsp" style=""></span>g confirmed and normal aminoaciduria. Abdominal ultrasound showed kidneys with normal corticomedullary differentiation.</p><p id="par0025" class="elsevierStylePara elsevierViewall">A Next Generation Sequencing (NGS) Ion AmpliSeq™ Custom Research Panel was used to study the coding regions and intronic flanking regions of the tubulopathy genes: <span class="elsevierStyleItalic">CLCNKB</span>, <span class="elsevierStyleItalic">CLCNKA</span>, <span class="elsevierStyleItalic">SCL12A3</span>, <span class="elsevierStyleItalic">SLC12A1</span>, <span class="elsevierStyleItalic">KCNJ1</span>, <span class="elsevierStyleItalic">BSND</span>, <span class="elsevierStyleItalic">CASR</span>, <span class="elsevierStyleItalic">CLDN16</span> and <span class="elsevierStyleItalic">CLDN19</span>. Libraries were prepared using Ion Ampliseq Library kit 2.0 (Life Technologies, CA, USA). Finally, DNA high-throughput sequencing was performed on a Personal Genome Machine (PGM) using the Ion PGM™ Hi-Q™ Sequencing Kit (Life Technologies) on the Ion 318™ sequencing chip (Life Technologies). Results evidenced a homozygous mutation c.361G>T (p.E121Ter; <a id="intr0005" class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=nucleotide&doptcmdl=genbank&term=NM_000339">NM_000339</a>) in the <span class="elsevierStyleItalic">SLC12A3</span> gene. This nucleotide change results in a premature stop codon, or a nonsense codon, in the transcribed mRNA, resulting in a truncated, incomplete, and usually nonfunctional protein. This variant has not been previously reported. Sanger sequencing of the exon 2 fragment confirmed that this patient was homozygous for the mutation.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In the <span class="elsevierStyleItalic">SLC12A3</span> gene, more than 180 mutations have been reported in GS patients.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Sequencing of the <span class="elsevierStyleItalic">SLC12A3</span> exons is required to search for mutations in most GS patients because there is not a prevalent mutation.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> Moreover, CLCNKB mutations may be found in some cases with clinical manifestations of GS, a fact that increases the complexity of the genetic study of GS.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">GS is inherited as an autosomal recessive trait, and homozygous and combined heterozygous mutations are expected.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> In our case, the single nucleotide polymorphism (SNP) detected along the <span class="elsevierStyleItalic">SLC12A3</span> gene was homozygous with the notion of consanguinity. The p.E121Ter variant was predicted to be likely pathogenic by at least three bioinformatic programs (SIFT, Polyphen and Mutation Taster). The patient came from an isolated and small village in Spain, and had a probable consanguinity between parents and a founder effect that has previously been reported in GS disease.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The mutations impair the activity of thiazide-sensitive sodium-chloride cotransporter encoded by <span class="elsevierStyleItalic">SLC12A3</span> and could be classified in five different types according to their effect on the protein. Large deletions including one or more exons of <span class="elsevierStyleItalic">SLC12A3</span> have also been detected<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> and the majority of these mutations should be included in this type 1 classification.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The definition of the <span class="elsevierStyleItalic">SLC12A3</span> genotype through description of new mutations may be a useful tool in the clinical characterization of GS and in genetic counseling of salt-losing tubulopathies.</p><p id="par0050" class="elsevierStylePara elsevierViewall">First, we suspected either GS or Bartter syndrome III the cause of hypokaliemia. Other causes such as vomiting or the use of diuretics were rejected due to history. The electrocardiographic alterations were probably secondary to hypokalemia. The slight glucosuria present at the diagnosis reminds us that hypomagnesemia and hypokaliemia were speculated to cause impaired glucose tolerance in GS patients. Our patient was not overweight, had normal to low blood pressure, and a proteinuria of 150<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h was monitored because of the podocyte dysfunction link described.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A new familial disorder characterized by hypokalemia, hypomagnesemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H.J. Gitelman" 1 => "J.B. Graham" 2 => "L.G. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 8 | 6 | 14 |
| 2024 Octubre | 48 | 47 | 95 |
| 2024 Septiembre | 49 | 24 | 73 |
| 2024 Agosto | 66 | 75 | 141 |
| 2024 Julio | 43 | 28 | 71 |
| 2024 Junio | 70 | 38 | 108 |
| 2024 Mayo | 75 | 37 | 112 |
| 2024 Abril | 54 | 39 | 93 |
| 2024 Marzo | 51 | 25 | 76 |
| 2024 Febrero | 52 | 32 | 84 |
| 2024 Enero | 34 | 31 | 65 |
| 2023 Diciembre | 35 | 32 | 67 |
| 2023 Noviembre | 51 | 39 | 90 |
| 2023 Octubre | 52 | 37 | 89 |
| 2023 Septiembre | 39 | 26 | 65 |
| 2023 Agosto | 44 | 24 | 68 |
| 2023 Julio | 61 | 48 | 109 |
| 2023 Junio | 53 | 33 | 86 |
| 2023 Mayo | 72 | 43 | 115 |
| 2023 Abril | 77 | 25 | 102 |
| 2023 Marzo | 60 | 30 | 90 |
| 2023 Febrero | 50 | 33 | 83 |
| 2023 Enero | 49 | 33 | 82 |
| 2022 Diciembre | 79 | 39 | 118 |
| 2022 Noviembre | 56 | 59 | 115 |
| 2022 Octubre | 109 | 62 | 171 |
| 2022 Septiembre | 45 | 40 | 85 |
| 2022 Agosto | 50 | 53 | 103 |
| 2022 Julio | 61 | 51 | 112 |
| 2022 Junio | 49 | 44 | 93 |
| 2022 Mayo | 49 | 38 | 87 |
| 2022 Abril | 48 | 57 | 105 |
| 2022 Marzo | 55 | 40 | 95 |
| 2022 Febrero | 52 | 38 | 90 |
| 2022 Enero | 53 | 46 | 99 |
| 2021 Diciembre | 48 | 36 | 84 |
| 2021 Noviembre | 54 | 47 | 101 |
| 2021 Octubre | 54 | 43 | 97 |
| 2021 Septiembre | 39 | 43 | 82 |
| 2021 Agosto | 50 | 56 | 106 |
| 2021 Julio | 41 | 35 | 76 |
| 2021 Junio | 42 | 39 | 81 |
| 2021 Mayo | 59 | 45 | 104 |
| 2021 Abril | 78 | 89 | 167 |
| 2021 Marzo | 62 | 37 | 99 |
| 2021 Febrero | 80 | 61 | 141 |
| 2021 Enero | 38 | 20 | 58 |
| 2020 Diciembre | 33 | 27 | 60 |
| 2020 Noviembre | 35 | 19 | 54 |
| 2020 Octubre | 39 | 31 | 70 |
| 2020 Septiembre | 43 | 30 | 73 |
| 2020 Agosto | 36 | 21 | 57 |
| 2020 Julio | 32 | 19 | 51 |
| 2020 Junio | 42 | 30 | 72 |
| 2020 Mayo | 74 | 23 | 97 |
| 2020 Abril | 31 | 25 | 56 |
| 2020 Marzo | 44 | 17 | 61 |
| 2020 Febrero | 33 | 28 | 61 |
| 2020 Enero | 52 | 29 | 81 |
| 2019 Diciembre | 32 | 29 | 61 |
| 2019 Noviembre | 52 | 30 | 82 |
| 2019 Octubre | 36 | 25 | 61 |
| 2019 Septiembre | 31 | 16 | 47 |
| 2019 Agosto | 33 | 25 | 58 |
| 2019 Julio | 36 | 29 | 65 |
| 2019 Junio | 58 | 33 | 91 |
| 2019 Mayo | 58 | 42 | 100 |
| 2019 Abril | 84 | 49 | 133 |
| 2019 Marzo | 107 | 43 | 150 |
| 2019 Febrero | 75 | 44 | 119 |
| 2019 Enero | 61 | 39 | 100 |
| 2018 Diciembre | 98 | 54 | 152 |
| 2018 Noviembre | 153 | 33 | 186 |
| 2018 Octubre | 74 | 15 | 89 |
| 2018 Septiembre | 64 | 20 | 84 |
| 2018 Agosto | 71 | 17 | 88 |
| 2018 Julio | 79 | 22 | 101 |
| 2018 Junio | 35 | 9 | 44 |
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