Short Original
A new SLC12A3 founder mutation (p.Val647Met) in Gitelman's syndrome patients of Roma ancestry
Una nueva mutación fundadora en SLC12A3 (p.Val647Met) en pacientes con síndrome de Gitelman de etnia gitana
Helena Gil-Peñaa,
, Eliecer Cotob,f, Fernando Santosa,f, Mar Espinoc, Jose Mª Cea Crespod, Giannis Chantzopoulose, Filadelfia Komianoue, Juan Gómezb, Belén Alonsob, Sara Iglesiasb, Cyrielle Treardf, Rosa Vargas-Poussouf, the Renaltube Group
Autor para correspondencia
a Dept. Pediatría-RENALTUBE Consortium, Hospital Universitario Central Asturias, Oviedo, Spain
b Dept. Genética Molecular-Red de Investigación Renal, Hospital Universitario Central Asturias, Oviedo, Spain
c Hospital Doce de Octubre, Madrid, Spain
d Hospital Severo Ochoa, Leganés, Spain
e Dept. Pediatrics, Aghia Sophia Children's Hospital, Athens, Greece
f Hôpital Européen Georges Pompidou, France
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Pediatría-RENALTUBE Consortium, Hospital Universitario Central Asturias, Oviedo, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Dept. Genética Molecular-Red de Investigación Renal, Hospital Universitario Central Asturias, Oviedo, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Doce de Octubre, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Hospital Severo Ochoa, Leganés, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Dept. Pediatrics, Aghia Sophia Children's Hospital, Athens, Greece" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Hôpital Européen Georges Pompidou, France" "etiqueta" => "f" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Una nueva mutación fundadora en <span class="elsevierStyleItalic">SLC12A3</span> (p.Val647Met) en pacientes con síndrome de Gitelman de etnia gitana" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1824 "Ancho" => 2334 "Tamanyo" => 240571 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Map of the <span class="elsevierStyleItalic">SLC12A3</span> showing the position of amino acid 647.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Gitelman's Syndrome (GS) is the most common primary renal tubular disorder, affecting approximately 1/40,000 Caucasians. GS is inherited as an autosomal recessive disease mainly linked to mutations in the <span class="elsevierStyleItalic">SLC12A3</span> gene (solute carrier family 12 sodium/chloride transporters, member 3), that encodes a thiazide-sensitive sodium-chloride co-transporter (NCC) protein that locates at the luminal membrane of the distal convoluted tubule in the kidney.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">1</span></a> GS is characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">2,3</span></a> The loss of function of the NCC channel leads to decreased sodium re-absorption and subsequently secondary volume depletion. The hypovolemia stimulates sodium re-absorption at the expense of increased potassium and hydrogen secretion, which results in hypokalemia and metabolic alkalosis.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">4</span></a> Hypocalciuria and hypomagnesaemia are also characteristic of GS, the latter being a likely consequence of the elevation of the excretion of magnesium in urine.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">5,6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Most of the GS patients are homozygous or heterozygous compound for rare private mutations. Due to the absence of common mutations, the sequencing of the full <span class="elsevierStyleItalic">SLC12A3</span> is required to uncover the genetic background of GS patients.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a> Moreover, some cases presenting as GS might carry mutations at the <span class="elsevierStyleItalic">CLCNKB</span> gene, a fact that increases the technical effort of the genetic study.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The Roma or Gypsies represent the largest and most widespread ethnic minority in Europe. Anthropological and genetic data support their origin in the Indian subcontinent.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">8</span></a> Although there was some mixture with their hosting populations, consanguinity is common among Gypsies and results in the presence of founder-mutations for several inherited disorders.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">9</span></a> To date, most of the reported Gypsy patients having GS are homozygous for the intron 9 +1G>T mutation (c.1180+1G>T).<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">10–12</span></a> Here, we describe a new <span class="elsevierStyleItalic">SLC12A3</span> mutation characteristic of Roma SG patients.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0020" class="elsevierStylePara elsevierViewall">We studied eight patients from five families diagnosed of GS (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The five families had a Roma ethnic background and traced their ancestry to the South-East European region, including the Spanish family whose ancestors emigrated from Romania two generations ago. The Spanish and Greek families were recruited through the Renaltube Consortium (<a href="http://www.renaltube.com/">www.renaltube.com</a>).<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Genetic study</span><p id="par0025" class="elsevierStylePara elsevierViewall">The search for <span class="elsevierStyleItalic">SLC12A3</span> and <span class="elsevierStyleItalic">CLCNKB</span> mutations was first performed in the index cases from families I and II. The two were negative for the intron 9 splicing mutation. The whole coding plus at least 5 intronic flanking nucleotides were sequenced through semiconductor Next Generation Sequencing (NGS) with the Ion Torrent Personal Genome Machine (PGM, Life Technologies), following a previously reported procedure.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">To confirm the putative mutations identified by NGS, the corresponding exons were amplified and sequenced by the Sanger method. This procedure was also used to determine the presence of the mutation in all the family members.</p><p id="par0035" class="elsevierStylePara elsevierViewall">To characterize the haplotypes linked to the <span class="elsevierStyleItalic">SLC12A3</span> mutation, five common single nucleotide polymorphisms were determined by Sanger sequencing of PCR fragments: rs5801 (c.1395C>T), rs2304483 (c.1670−8T>C), rs13306676 (c.2179−8C>T), rs34772420 (c.2748−13T>C), and rs2289115 (c.2951+13C>T). In families I and II we also genotyped an intron 9 repeat polymorphism.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Clinical data</span><p id="par0040" class="elsevierStylePara elsevierViewall">Family I had several GS patients in two generations. The index case (PI.1) was the father of three children with mild clinical features of GS. The father was diagnosed in the adolescence whereas the three siblings were diagnosed before the age of two years. Three brothers and one sister of the index case presented also GS findings such as hypokalemia, hypomagnesaemia and elevated bicarbonate serum values with a blood pH<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>7.35 (data not showed).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Genotype</span><p id="par0045" class="elsevierStylePara elsevierViewall">The NGS of <span class="elsevierStyleItalic">SLC12A3</span> and <span class="elsevierStyleItalic">CLCNKB</span> in the index cases from families I and II revealed the presence of a nucleotide variant in exon 16 of <span class="elsevierStyleItalic">SLC12A3</span> (c.1939G>A) that would result in a missense amino acid change (p.Val647Met). This variant is predicted to be pathogenic/deleterious by the bioinformatic programs SIFT (<a href="http://sift.jcvi.org/">http://sift.jcvi.org</a>) and Polyphen (<a href="http://genetics.bwh.harvard.edu/pph2">http://genetics.bwh.harvard.edu/pph2</a>). The Sanger sequencing of exon 16 fragments showed that these patients were homozygous for the mutation, and we also determined the mutation genotype in all the family members (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The analysis of the five <span class="elsevierStyleItalic">SLC12A3</span> SNPs showed that the p.647 Val mutation was in the same haplotype in the five families (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0055" class="elsevierStylePara elsevierViewall">More than 180 mutations in <span class="elsevierStyleItalic">SLC12A3</span> gene have been reported in GS patients.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a> There is not a prevalent mutation, and this means that the sequencing of the 26 <span class="elsevierStyleItalic">SLC12A3</span> exons is required to search for mutations in most of the GS patients.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">15,16</span></a> Moreover, <span class="elsevierStyleItalic">CLCNKB</span> mutations may be found in some cases with clinical manifestations of GS, a fact that increases the complexity of the genetic study of GS. Thus, the discovery of mutations common in an ethnic group will facilitate the genetic analysis by limiting the sequencing to one or few exons.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">10</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In this article we present Gypsy cases from Spain and Greece with the same mutation in the SLC12A3 gene. Patients were recruited through the Renaltube Consortium<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">13</span></a> which collects data from patients worldwide in an attempt to better define the clinical profile and the genetic background of renal tubulopathies. To date, >50 Gypsi GS patients are included in the Renaltube database and most of these patients are homozygous for the intron 9 splicing mutation. The index cases of Families I and II, were subjected to NGS to search for new <span class="elsevierStyleItalic">SLC12A3</span> mutations, resulting in the identification of p.Val647Met. The p.Val647Met variant was predicted to be pathogenic with at least two bioinformatic programs (SIFT and Polyphen). This missense change locates at the intracellular carboxy-end of the protein (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), where other GS mutations have been found and aminoacids at this region are conserved not only among species but also in other human channels such us bumetanide-sensitive cotransporter (<span class="elsevierStyleItalic">SLC12A2</span> gene).<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">17</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The p.Val647Met mutation had been previously reported by Vargas-Poussou et al. in one GS patient (PV.1) compound heteorzygous for this variant and the intron 9 mutation.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a> Thus, the two families we studied and the three previously reported by Vargas et al.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a> had a common Gipsy genetic background and traced their ancestry to South-Eastern Europe. The p.Val647Met was linked to the same <span class="elsevierStyleItalic">SLC12A3</span> polymorphisms in the 5 families, a fact that strongly supports a common origin for this new Gipsy SG mutation.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion, we report a new <span class="elsevierStyleItalic">SLC12A3</span> founder mutation among GS patients of Gypsy background, p.Val647Met. This mutation was associated with typical clinical features of GS, either in homozygosity or in combination with the intron 9+1G>A mutation. Our finding facilitates the diagnosis of GS in Gypsy patients.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Compliance with ethical standards</span><p id="par0075" class="elsevierStylePara elsevierViewall">All the patients/participants in the study gave their informed consent, approved by the Ethical Committee of Hospital Universitario Central Asturias.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres874608" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec863000" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres874609" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec863001" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Genetic study" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Clinical data" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Genotype" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Compliance with ethical standards" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "xack291660" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-25" "fechaAceptado" => "2017-01-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec863000" "palabras" => array:4 [ 0 => "Gitelman's syndrome" 1 => "<span class="elsevierStyleItalic">SLC12A3</span> gene" 2 => "Gypsy patients" 3 => "Roma genetic background" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec863001" "palabras" => array:4 [ 0 => "Síndrome de Gitelman" 1 => "Gen <span class="elsevierStyleItalic">SLC12A3</span>" 2 => "Pacientes de etnia gitana" 3 => "Antecedentes genéticos gitanos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Gitelman's syndrome (GS) is an autosomal recessive disorder caused by mutations in the <span class="elsevierStyleItalic">SLC12A3</span> gene. GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Most of the reported patients of Roma ancestry are homozygous for an <span class="elsevierStyleItalic">SLC12A3</span> intron 9 frameshifting mutation (c.1180+1G>T). Some forms of Bartter's syndrome result from mutations in the <span class="elsevierStyleItalic">CLNCKB</span> gene and clinically overlap with GS.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To characterize a second <span class="elsevierStyleItalic">SLC12A3</span> mutation in Roma patients negative for the intron 9 variant.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">SLC12A3</span> and <span class="elsevierStyleItalic">CLNCKB</span> genes were analyzed by next-generation sequencing in two Spanish and Greek gypsy patients who were negative for the intron 9 splicing mutation. Sanger sequencing was performed to confirm the putative mutations in patients and family members.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We identified a missense variant (p.Val647Met, c.1939G>A) in both cases, and both were homozygous for Met. This mutation was also found in three additional patients; two homozygous and one heterozygous compound with the intron 9 splicing mutation. This new <span class="elsevierStyleItalic">SLC12A3</span> mutation seems to be characteristic of gipsy GS patients and was linked to the same haplotype in all cases, supporting a founder origin. All the patients showed biochemical features characteristic of GS.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">We report a second founder mutation among GS patients of Roma ethnic background. The direct screening of this mutation would facilitate the characterization of patients who are negative for the more common intron 9 +1G>T mutation.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El síndrome de Gitelman (SG) es un trastorno autosómico recesivo causado por las mutaciones en el gen <span class="elsevierStyleItalic">SLC12A3.</span> El SG se caracteriza por una alcalosis metabólica hipopotasémica, hipomagnesemia e hipocalciuria. La mayoría de los pacientes de etnia gitana notificados son homocigotos para la mutación con desplazamiento del marco de lectura del intrón 9 de <span class="elsevierStyleItalic">SLC12A3</span> (c.1180<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T). Algunas formas del síndrome de Bartter proceden de las mutaciones del gen <span class="elsevierStyleItalic">CLNCKB</span> y se solapan clínicamente con el SG.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Determinar las características de una segunda mutación en <span class="elsevierStyleItalic">SLC12A3</span> en pacientes de etnia gitana con resultados negativos en la variante intrón 9.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se analizaron los genes <span class="elsevierStyleItalic">SLC12A3</span> y <span class="elsevierStyleItalic">CLNCKB</span> mediante secuenciación de nueva generación en 2 pacientes –uno español y otro griego– de etnia gitana con resultados negativos en la mutación de empalme del intrón 9. Se llevó a cabo una secuenciación de Sanger para confirmar las supuestas mutaciones en los pacientes y sus familiares.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Se identificó una variante con cambio de sentido (p.Val647Met, c.1939G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>A) en ambos casos, y ambos eran homocigotos con respecto a Met. También se observó esta mutación en 3 pacientes adicionales, 2 homocigotos y uno heterocigoto compuesto con la mutación del intrón 9. Esta nueva mutación del <span class="elsevierStyleItalic">SLC12A3</span> parece ser característica de los pacientes con SG de etnia gitana y se relacionó con el mismo haplotipo en todos los casos, lo que indica un origen fundador. Todos los pacientes presentaron rasgos bioquímicos propios del SG.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusión</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Informamos de una segunda mutación fundadora en los pacientes con SG de etnia gitana. El cribado genético directo de esta mutación facilitará la determinación de las características de los pacientes con resultados negativos en la mutación del intrón 9<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T, que es más frecuente.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3016 "Ancho" => 2334 "Tamanyo" => 300128 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Pedigrees of the five families. A and B represents the haplotypes containing the p.647 Met. *Intron 9 GAT-<span class="elsevierStyleItalic">repeats</span> not available.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1824 "Ancho" => 2334 "Tamanyo" => 240571 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Map of the <span class="elsevierStyleItalic">SLC12A3</span> showing the position of amino acid 647.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">K<span class="elsevierStyleSup">+</span>: potassium; Mg<span class="elsevierStyleSup">2+</span>: magnesium; HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">−</span>: bicarbonate; Val: valine; Met: methionine. NA: data not available.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Kindred \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age at diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">pH \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">HCO<span class="elsevierStyleInf">3</span><span class="elsevierStyleSup">−</span> (mEq/L) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">K<span class="elsevierStyleSup">+</span> (mEq/L) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mg<span class="elsevierStyleSup">2+</span> (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Mutations in <span class="elsevierStyleItalic">SLC12A3</span> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PI.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PI.1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PI.1.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PI.1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PII.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PIII.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.00 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PIV.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/p.Val647Met \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Family V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PV.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Val647Met/Intron 9 +1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1476021.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Serum biochemistry and genetic data of the affected members in the five families.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0090" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.B. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 11 | 11 | 22 |
| 2024 Octubre | 81 | 49 | 130 |
| 2024 Septiembre | 88 | 34 | 122 |
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| 2024 Febrero | 88 | 50 | 138 |
| 2024 Enero | 65 | 30 | 95 |
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| 2023 Noviembre | 78 | 40 | 118 |
| 2023 Octubre | 90 | 78 | 168 |
| 2023 Septiembre | 77 | 67 | 144 |
| 2023 Agosto | 66 | 42 | 108 |
| 2023 Julio | 71 | 47 | 118 |
| 2023 Junio | 53 | 58 | 111 |
| 2023 Mayo | 86 | 58 | 144 |
| 2023 Abril | 44 | 27 | 71 |
| 2023 Marzo | 68 | 31 | 99 |
| 2023 Febrero | 54 | 40 | 94 |
| 2023 Enero | 62 | 42 | 104 |
| 2022 Diciembre | 102 | 42 | 144 |
| 2022 Noviembre | 64 | 59 | 123 |
| 2022 Octubre | 109 | 84 | 193 |
| 2022 Septiembre | 141 | 46 | 187 |
| 2022 Agosto | 101 | 59 | 160 |
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| 2022 Junio | 56 | 60 | 116 |
| 2022 Mayo | 97 | 46 | 143 |
| 2022 Abril | 80 | 67 | 147 |
| 2022 Marzo | 109 | 75 | 184 |
| 2022 Febrero | 582 | 47 | 629 |
| 2022 Enero | 64 | 60 | 124 |
| 2021 Diciembre | 61 | 44 | 105 |
| 2021 Noviembre | 60 | 37 | 97 |
| 2021 Octubre | 52 | 61 | 113 |
| 2021 Septiembre | 54 | 59 | 113 |
| 2021 Agosto | 49 | 55 | 104 |
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| 2021 Enero | 76 | 48 | 124 |
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| 2020 Noviembre | 56 | 34 | 90 |
| 2020 Octubre | 40 | 39 | 79 |
| 2020 Septiembre | 49 | 38 | 87 |
| 2020 Agosto | 58 | 43 | 101 |
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| 2019 Septiembre | 74 | 30 | 104 |
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| 2018 Diciembre | 268 | 69 | 337 |
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| 2018 Febrero | 170 | 12 | 182 |
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| 2017 Octubre | 73 | 22 | 95 |
| 2017 Septiembre | 96 | 22 | 118 |
| 2017 Agosto | 116 | 24 | 140 |
| 2017 Julio | 75 | 19 | 94 |
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| 2017 Mayo | 70 | 13 | 83 |
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