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New mutation in 2 paediatric patients with Alport syndrome. Prognostic significance of genotype
Alteración genética no descrita previamente en 2 pacientes pediátricas con síndrome de Alport. Influencia pronóstica del genotipo
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Influencia pronóstica del genotipo" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "352" "paginaFinal" => "354" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "New mutation in 2 pediatric patients with Alport syndrome. Prognostic significance of genotype" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1784 "Ancho" => 3334 "Tamanyo" => 543791 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Gen <span class="elsevierStyleItalic">COL4A5</span> con presencia de mutación no descrita previamente. El electroferograma muestra mutación truncante, con codón <span class="elsevierStyleItalic">stop</span> prematuro en posición 184, dando lugar a una proteína de tamaño anómalo (183 en lugar de 1.685 aminoácidos).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Laura Butragueño Laiseca, Elisabet Ars, Ana B. Martínez López, Olalla Álvarez Blanco, Juan J. Tejado Balsera, Augusto Luque de Pablos" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Laura" "apellidos" => "Butragueño Laiseca" ] 1 => array:2 [ "nombre" => "Elisabet" "apellidos" => "Ars" ] 2 => array:2 [ "nombre" => "Ana B." "apellidos" => "Martínez López" ] 3 => array:2 [ "nombre" => "Olalla" "apellidos" => "Álvarez Blanco" ] 4 => array:2 [ "nombre" => "Juan J." 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Prognostic significance of genotype" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "352" "paginaFinal" => "354" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Laura Butragueño Laiseca, Elisabet Ars, Ana B. Martínez López, Olalla Álvarez Blanco, Juan J. Tejado Balsera, Augusto Luque de Pablos" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Laura" "apellidos" => "Butragueño Laiseca" "email" => array:1 [ 0 => "laura_bl@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Elisabet" "apellidos" => "Ars" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Ana B." "apellidos" => "Martínez López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Olalla" "apellidos" => "Álvarez Blanco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Juan J." "apellidos" => "Tejado Balsera" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Augusto" "apellidos" => "Luque de Pablos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Sección de Nefrología Pediátrica, Servicio de Pediatría, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Laboratorio de Biología Molecular, Fundació Puigvert, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Alteración genética no descrita previamente en 2 pacientes pediátricas con síndrome de Alport. Influencia pronóstica del genotipo" ] ] "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" => 1784 "Ancho" => 3334 "Tamanyo" => 542550 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">COL4A5</span>gene with presence of new mutation. The electropherogram shows a truncating mutation, with a premature <span class="elsevierStyleItalic">stop</span> codon at position 184, giving rise to a protein of anomalous size (183 instead of 1685 amino acids).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Alport syndrome (AS), first described in 1927,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> is a genetic disorder that affects the basement membranes. Its estimated prevalence is 1/5000–1/10,000.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> It is characterised by the presence of haematuria associated with sensorineural deafness, ocular lesions and alterations of the glomerular basement membrane that eventually lead to end-stage renal disease (ESRD) and it is responsible for 1–2% of patients with ESRD in western countries.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In AS, the alteration is localised in the glomerular basement membrane, which comprises a type <span class="elsevierStyleSmallCaps">IV</span> collagen network formed by α3, α4 and α5 chain trimers coded by the genes <span class="elsevierStyleItalic">COL4A3</span>, <span class="elsevierStyleItalic">COL4A4</span> and <span class="elsevierStyleItalic">COL4A5</span>, respectively.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> In most cases (80–85%), AS is transmitted by X-linked inheritance (SALX) with mutations in the <span class="elsevierStyleItalic">COL4A5</span> gene. Males are more severely affected since they present the mutation in hemizygosity, while women are heterozygous carriers of the altered gene with a generally less severe clinical involvement.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> The remaining 10–15% are affected by recessive autosomal inheritance <span class="elsevierStyleItalic">with mutations of the gene COL4A3</span> or <span class="elsevierStyleItalic">COL4A4</span>.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Traditionally, a third type of autosomal dominant inheritance was included, which today falls under “collagen type IV (α3–α4) nephropathy”.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We present two cases of paediatric AS; two sisters, carriers of a new X-linked mutation in the <span class="elsevierStyleItalic">COL4A5</span> gene.</p><p id="par0020" class="elsevierStylePara elsevierViewall">A 13-year-old girl, monitored since age 1 due to micro-haematuria and non-nephrotic proteinuria. Family history (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>): 45-year-old mother has presented proteinuria and haematuria since age 11, currently with normal glomerular filtration, requiring hearing aids since age 37. Maternal grandmother diagnosed with nephrotic syndrome at age 14, deceased on haemodialysis programme due to a non-specific nephropathy. No history of kidney disease in the paternal family.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Due to clinical and family history, a kidney biopsy was performed at age 5, with an optical microscopy revealing a focal segmental glomerulosclerosis. Electron microscopy showed alterations in the basement membrane of the capillaries with a difference in thickness and a parallel rupture, creating grooves with disappearance at certain points of the lamina densa. All of this pointed to a kidney disorder as part of AS. Hearing test was normal.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Due to the family's history, her sister (three years younger) was studied from age 2, detecting non-nephrotic proteinuria and micro-haematuria with no hearing alterations.</p><p id="par0035" class="elsevierStylePara elsevierViewall">No kidney biopsy was performed since she had a similar clinical/analytical profile to her sister. At present, both maintain a normal glomerular filtration rate and are under treatment with angiotensin II receptor antagonists.</p><p id="par0040" class="elsevierStylePara elsevierViewall">A genetic study was performed on the mother and on both sisters, with all three being heterozygous carriers of the mutation <span class="elsevierStyleItalic">COL4A5</span> c.412delG, p.(Gly138Valfs*17), undescribed to this moment, confirming the clinical suspicion of SALX (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). This is a <span class="elsevierStyleItalic">frameshift</span> mutation that involves changing the reading pattern on glycine amino acid 138 resulting in the generation of a premature translation termination codon at position 184. This mutation is expected to produce a protein of an anomalous size, with only 183 amino acids rather than the 1685 found in the normal protein (α5 chain of type<span class="elsevierStyleSmallCaps">IV</span> collagen, protein coded by the <span class="elsevierStyleItalic">COL4A5</span> gene). This mutation has yet to be described in the literature and it does not appear in <span class="elsevierStyleItalic">COL4A5</span> gene mutation databases. Since it is a truncating mutation, it can definitely be considered pathogenic and, therefore, the cause of the nephropathy in this family.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">More than 1000 <span class="elsevierStyleItalic">COL4A5</span> gene mutations in patients and families with SALX have been published or reported in mutational databases (The Human Gene Mutation Database [<a href="http://www.hgmd.cf.ac.uk/ac/index.php">http://www.hgmd.cf.ac.uk/ac/index.php</a>]; Leiden Open Variation Database [LOVD]; ARUP [<a href="http://www.arup.utah.edu/database/">http://www.arup.utah.edu/database/</a>]). These mutations include large rearrangements (7%), small deletions (14%, as is the case with our patients) and insertions/duplications (6%), <span class="elsevierStyleItalic">missense</span> mutations (43%), <span class="elsevierStyleItalic">nonsense</span> mutations (6%) and <span class="elsevierStyleItalic">splicing</span> mutations (23%).<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">COL4A5</span> genotype has a significant predictive effect on the course of kidney disease in males, determining the likelihood of progression to ESRD in the second decade of life. Truncating mutations generally have a worse prognosis than <span class="elsevierStyleItalic">missense</span> mutations (90% in large deletions, <span class="elsevierStyleItalic">nonsense</span>, translocations; 70% in <span class="elsevierStyleItalic">splicing</span> mutations; 50% in <span class="elsevierStyleItalic">missense</span> mutations).<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,9</span></a> The <span class="elsevierStyleItalic">COL4A5</span> genotype also has an influence on sensorineural deafness, with deafness occurring at age 30 in 90% of males with deletions, <span class="elsevierStyleItalic">nonsense</span> and <span class="elsevierStyleItalic">splicing</span> mutations compared to 60% with <span class="elsevierStyleItalic">missense</span> mutations.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,9</span></a> Likewise, patients with truncating or <span class="elsevierStyleItalic">splicing</span> mutations will develop visual alterations 2–4 times more often than those with <span class="elsevierStyleItalic">missense</span> mutations.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9,10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">This genotype–phenotype correlation is not as apparent in females, probably due to the inactivation phenomena of the altered X chromosome. However, it is equally influential given that (for example) women with SALX and renal damage tend to have more frequent truncating mutations.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Genetic diagnosis is therefore an essential tool both for confirming the diagnosis and for ascertaining the mechanism of inheritance with a view to providing genetic counselling. The existing genetic mutation may even determine the evolutionary path of the disease. As such, we see genetic study as essential for an early diagnosis and to establish an individualised treatment plan that prevents deterioration of the glomerular basement membrane and the consequent renal damage.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0065" class="elsevierStylePara elsevierViewall">No funding was received for this work.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Butragueño Laiseca L, Ars E, Martínez López AB, Álvarez Blanco O, Tejado Balsera JJ, Luque de Pablos A. Alteración genética no descrita previamente en 2 pacientes pediátricas con síndrome de Alport. Influencia pronóstica del genotipo. Nefrologia. 2017;37:352–354.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 964 "Ancho" => 1008 "Tamanyo" => 62429 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Family history. The arrow indicates the index case. Sister and mother both carriers of the mutation. Maternal uncle healthy. Affected grandmother deceased.</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" => 1784 "Ancho" => 3334 "Tamanyo" => 542550 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">COL4A5</span>gene with presence of new mutation. The electropherogram shows a truncating mutation, with a premature <span class="elsevierStyleItalic">stop</span> codon at position 184, giving rise to a protein of anomalous size (183 instead of 1685 amino acids).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hereditary familial congenital haemorrhagic nephritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 5 | 15 |
| 2024 October | 56 | 47 | 103 |
| 2024 September | 66 | 32 | 98 |
| 2024 August | 88 | 59 | 147 |
| 2024 July | 52 | 29 | 81 |
| 2024 June | 80 | 37 | 117 |
| 2024 May | 75 | 39 | 114 |
| 2024 April | 99 | 48 | 147 |
| 2024 March | 67 | 34 | 101 |
| 2024 February | 75 | 36 | 111 |
| 2024 January | 54 | 23 | 77 |
| 2023 December | 70 | 40 | 110 |
| 2023 November | 98 | 47 | 145 |
| 2023 October | 83 | 52 | 135 |
| 2023 September | 110 | 48 | 158 |
| 2023 August | 77 | 41 | 118 |
| 2023 July | 88 | 35 | 123 |
| 2023 June | 71 | 22 | 93 |
| 2023 May | 120 | 54 | 174 |
| 2023 April | 70 | 42 | 112 |
| 2023 March | 82 | 24 | 106 |
| 2023 February | 77 | 23 | 100 |
| 2023 January | 71 | 29 | 100 |
| 2022 December | 86 | 35 | 121 |
| 2022 November | 112 | 60 | 172 |
| 2022 October | 113 | 81 | 194 |
| 2022 September | 74 | 37 | 111 |
| 2022 August | 129 | 53 | 182 |
| 2022 July | 114 | 56 | 170 |
| 2022 June | 63 | 50 | 113 |
| 2022 May | 62 | 39 | 101 |
| 2022 April | 93 | 54 | 147 |
| 2022 March | 112 | 64 | 176 |
| 2022 February | 72 | 52 | 124 |
| 2022 January | 64 | 53 | 117 |
| 2021 December | 81 | 38 | 119 |
| 2021 November | 43 | 52 | 95 |
| 2021 October | 61 | 47 | 108 |
| 2021 September | 30 | 31 | 61 |
| 2021 August | 37 | 40 | 77 |
| 2021 July | 43 | 31 | 74 |
| 2021 June | 25 | 28 | 53 |
| 2021 May | 38 | 37 | 75 |
| 2021 April | 107 | 42 | 149 |
| 2021 March | 50 | 46 | 96 |
| 2021 February | 61 | 38 | 99 |
| 2021 January | 43 | 73 | 116 |
| 2020 December | 41 | 114 | 155 |
| 2020 November | 54 | 23 | 77 |
| 2020 October | 39 | 23 | 62 |
| 2020 September | 37 | 15 | 52 |
| 2020 August | 40 | 8 | 48 |
| 2020 July | 37 | 18 | 55 |
| 2020 June | 34 | 18 | 52 |
| 2020 May | 43 | 13 | 56 |
| 2020 April | 33 | 21 | 54 |
| 2020 March | 39 | 10 | 49 |
| 2020 February | 49 | 27 | 76 |
| 2020 January | 36 | 20 | 56 |
| 2019 December | 50 | 19 | 69 |
| 2019 November | 51 | 21 | 72 |
| 2019 October | 53 | 16 | 69 |
| 2019 September | 56 | 13 | 69 |
| 2019 August | 44 | 20 | 64 |
| 2019 July | 50 | 18 | 68 |
| 2019 June | 42 | 21 | 63 |
| 2019 May | 41 | 20 | 61 |
| 2019 April | 48 | 42 | 90 |
| 2019 March | 37 | 25 | 62 |
| 2019 February | 45 | 25 | 70 |
| 2019 January | 33 | 16 | 49 |
| 2018 December | 174 | 41 | 215 |
| 2018 November | 229 | 21 | 250 |
| 2018 October | 198 | 24 | 222 |
| 2018 September | 126 | 24 | 150 |
| 2018 August | 71 | 17 | 88 |
| 2018 July | 57 | 12 | 69 |
| 2018 June | 83 | 17 | 100 |
| 2018 May | 96 | 18 | 114 |
| 2018 April | 174 | 11 | 185 |
| 2018 March | 147 | 17 | 164 |
| 2018 February | 213 | 9 | 222 |
| 2018 January | 122 | 9 | 131 |
| 2017 December | 214 | 8 | 222 |
| 2017 November | 77 | 13 | 90 |
| 2017 October | 50 | 10 | 60 |
| 2017 September | 67 | 8 | 75 |
| 2017 August | 84 | 6 | 90 |
| 2017 July | 71 | 9 | 80 |
| 2017 June | 48 | 4 | 52 |
| 2017 May | 55 | 10 | 65 |
| 2017 April | 49 | 14 | 63 |
| 2017 March | 8 | 1 | 9 |
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