Scientific Letter
New genetic mutation associated with Pierson syndrome
Nueva mutación genética asociada con el síndrome de pierson
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class="elsevierStyleTextfn">Scientific Letter</span>" "titulo" => "New genetic mutation associated with Pierson syndrome" "tieneTextoCompleto" => true "saludo" => "<span class="elsevierStyleItalic">Dear Editor:</span>" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "321" "paginaFinal" => "322" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Lorena Peña-González, Pilar Guerra-García, María Teresa Sánchez-Calvín, Fatima Delgado-Ledesma, Concepción de Alba-Romero" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Lorena" "apellidos" => "Peña-González" "email" => array:1 [ 0 => "lorena.penag@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => 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mutación genética asociada con el síndrome de pierson" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We present the case of a female newborn, unremarkable pregnancy, born at term. Low birth weight for gestational age. Parents were first cousins, originally from Pakistan, with two previous healthy sons. On initial examination she was found to have bilateral megalocornea and microcoria.</p><p id="par0010" class="elsevierStylePara elsevierViewall">During her first week of life, she developed lethargy, oxygen desaturations and bradycardia. Blood tests showed severe metabolic acidosis (pH 7.17, PCO2 51<span class="elsevierStyleHsp" style=""></span>mmHg, HCO<span class="elsevierStyleInf">3</span> 18.6<span class="elsevierStyleHsp" style=""></span>mmol/L, BE – 9<span class="elsevierStyleHsp" style=""></span>mmol/L) with hypoproteinemia, hypoalbuminemia (total protein 2.8<span class="elsevierStyleHsp" style=""></span>g/dl, albumin 1.4<span class="elsevierStyleHsp" style=""></span>g/dl) and increased creatinine (1.03<span class="elsevierStyleHsp" style=""></span>mg/dl). Urine tests showed proteinuria (nephrotic range – 600<span class="elsevierStyleHsp" style=""></span>mg/dl). A brain MRI showed mild periventricular white-matter signal alterations. These findings, added to the ocular malformations, raised the suspicion of Pierson syndrome (PS).</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient was managed symptomatically. Despite supporting measures, she developed progressive renal failure (maximum creatinine 3.07<span class="elsevierStyleHsp" style=""></span>mg/dl and urea 142<span class="elsevierStyleHsp" style=""></span>mg/dl), with multiple acid–base and electrolyte disorders, anemia and uncontrolled systemic arterial hypertension.</p><p id="par0020" class="elsevierStylePara elsevierViewall">At the age of two months, she progressed to cardiogenic shock that did not respond to medical treatment. Due to the clinical course of the disease and the dismal prognosis, withdrawal of life support was agreed, with the patient dying within several hours.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Genetic testing was performed on our patient. A blood sample in K3-EDTA was obtained, and DNA from lymphocytes was extracted for molecular studies. Amplified DNA fragments of the 32 coding exons and flanking intronic regions of the LAMB2 gene were obtained by PCR. These were subjected to mutational screening by direct sequencing using an Applied Biosystem® 3500 DX Genetic Analyzer, and compared to the consensus sequence of the transcript <a id="intr0010" class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=nucleotide&doptcmdl=genbank&term=NM_002292.3">NM_002292.3</a>. A suspected homozygous variant c.1405<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>2dupT in the intron 10 of the LAMB2 gene was detected (subsequently confirmed by finding the same mutation in heterozygosis in both parents). This mutation has not been previously described as a polymorphism or associated with PS in the databases searched (HGMD®, LOVD, ExAC browser and 1000 genomas). However, this mutation could affect the splice donor site in intron 10, producing an aberrant splicing and a malfunctioning protein.</p><p id="par0030" class="elsevierStylePara elsevierViewall">PS is a rare and fatal autosomal recessive disorder. Characteristic findings include congenital nephrotic syndrome and ocular malformations. It is due to mutations in the LAMB2 gene, found in chromosome 3p21, which encodes laminin-beta-2 protein. Laminin-beta-2 is expressed in the glomerular basement membrane, where it plays a role in anchoring and differentiation of podocyte foot processes.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> If this membrane integrity is lost, massive proteinuria and hypoalbuminemia develops, leading to end-stage renal disease and, in most cases, death in the first months of life. Laminin-beta-2 is also found in the connective tissue of ocular and nerve structures, causing a broad range of ocular and neurologic impairment.</p><p id="par0035" class="elsevierStylePara elsevierViewall">There are currently 52 known mutations associated with PS (HGMD®). Some of the known mutations in the LAMB2 gene have genotype/phenotype correlation. Different mutations have been described – some predict a total loss of function of the protein while others lead to some remaining function.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">2–4</span></a> The mutation found in our patient has not been previously described, neither as polymorphism nor as associated with PS. The bioinformatic predictors Mutation T@sting and Human Splicing Finder report that this mutation most probably affects the splicing region in intron 10 of LAMB2, predicting an aberrant splicing and a malfunction of the protein laminin-beta-2. Moreover, pathogenic mutations in c.1405<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>A<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a> and c.1405<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>3A<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T6<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a> have already been reported, which would affect the same splicing region as the mutation in our patient, supporting its pathogenicity.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In autosomal recessive (AR) diseases de novo mutations are rare, and there are normally no manifestations of the disease in heterozygous individuals. If we consider this mutation as potentially pathogenic, taking into account the AR inheritance of the disease, the presence of this mutation in homozygosis is most probably the cause of the disease in our patient.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In these diseases, knowing the genetic cause of the disease is important to be able to establish the risk of recurrence, offer appropriate genetic counseling and options to prevent recurrence in a family. In AR diseases, where both parents are healthy carriers, the risk of recurrence is 25%.</p><p id="par0050" class="elsevierStylePara elsevierViewall">To confirm the pathogenicity of this mutation, further case reports of patients with PS and this same mutation should be reported as well as functional assays which are not always available. If this is confirmed, it is probable that this specific mutation is associated with a severe phenotype as our patient's disease had neonatal-onset, with ocular, renal and neurologic findings and has had a dismal outcome at the age of two months.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Peña-González L, Guerra-García P, Sánchez-Calvín MT, Delgado-Ledesma F, de Alba-Romero C. Nueva mutación genética asociada con el síndrome de pierson. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 8 | 16 |
| 2024 October | 50 | 41 | 91 |
| 2024 September | 43 | 34 | 77 |
| 2024 August | 60 | 52 | 112 |
| 2024 July | 37 | 34 | 71 |
| 2024 June | 51 | 40 | 91 |
| 2024 May | 35 | 31 | 66 |
| 2024 April | 38 | 22 | 60 |
| 2024 March | 39 | 43 | 82 |
| 2024 February | 31 | 31 | 62 |
| 2024 January | 29 | 20 | 49 |
| 2023 December | 23 | 23 | 46 |
| 2023 November | 21 | 23 | 44 |
| 2023 October | 41 | 27 | 68 |
| 2023 September | 20 | 17 | 37 |
| 2023 August | 25 | 18 | 43 |
| 2023 July | 32 | 24 | 56 |
| 2023 June | 34 | 25 | 59 |
| 2023 May | 57 | 24 | 81 |
| 2023 April | 31 | 16 | 47 |
| 2023 March | 35 | 24 | 59 |
| 2023 February | 41 | 19 | 60 |
| 2023 January | 38 | 18 | 56 |
| 2022 December | 40 | 26 | 66 |
| 2022 November | 57 | 32 | 89 |
| 2022 October | 64 | 53 | 117 |
| 2022 September | 42 | 26 | 68 |
| 2022 August | 47 | 42 | 89 |
| 2022 July | 40 | 31 | 71 |
| 2022 June | 44 | 30 | 74 |
| 2022 May | 39 | 44 | 83 |
| 2022 April | 49 | 22 | 71 |
| 2022 March | 78 | 41 | 119 |
| 2022 February | 42 | 19 | 61 |
| 2022 January | 56 | 33 | 89 |
| 2021 December | 43 | 49 | 92 |
| 2021 November | 48 | 41 | 89 |
| 2021 October | 69 | 71 | 140 |
| 2021 September | 36 | 41 | 77 |
| 2021 August | 31 | 51 | 82 |
| 2021 July | 37 | 26 | 63 |
| 2021 June | 49 | 54 | 103 |
| 2021 May | 46 | 38 | 84 |
| 2021 April | 120 | 66 | 186 |
| 2021 March | 59 | 39 | 98 |
| 2021 February | 48 | 29 | 77 |
| 2021 January | 57 | 32 | 89 |
| 2020 December | 67 | 33 | 100 |
| 2020 November | 38 | 22 | 60 |
| 2020 October | 50 | 21 | 71 |
| 2020 September | 35 | 15 | 50 |
| 2020 August | 43 | 14 | 57 |
| 2020 July | 49 | 13 | 62 |
| 2020 June | 43 | 18 | 61 |
| 2020 May | 56 | 19 | 75 |
| 2020 April | 49 | 12 | 61 |
| 2020 March | 29 | 12 | 41 |
| 2020 February | 40 | 17 | 57 |
| 2020 January | 32 | 9 | 41 |
| 2019 December | 42 | 16 | 58 |
| 2019 November | 40 | 12 | 52 |
| 2019 October | 32 | 15 | 47 |
| 2019 September | 31 | 10 | 41 |
| 2019 August | 48 | 16 | 64 |
| 2019 July | 45 | 17 | 62 |
| 2019 June | 45 | 18 | 63 |
| 2019 May | 68 | 22 | 90 |
| 2019 April | 62 | 23 | 85 |
| 2019 March | 40 | 12 | 52 |
| 2019 February | 48 | 20 | 68 |
| 2019 January | 40 | 15 | 55 |
| 2018 December | 57 | 24 | 81 |
| 2018 November | 69 | 33 | 102 |
| 2018 October | 111 | 30 | 141 |
| 2018 September | 60 | 15 | 75 |
| 2018 August | 2 | 0 | 2 |
| 2018 July | 1 | 0 | 1 |
| 2018 June | 2 | 0 | 2 |
| 2018 May | 2 | 0 | 2 |
| 2018 April | 31 | 0 | 31 |
| 2018 March | 46 | 0 | 46 |
| 2018 February | 19 | 0 | 19 |
| 2018 January | 31 | 0 | 31 |
| 2017 December | 23 | 0 | 23 |
| 2017 November | 16 | 0 | 16 |
| 2017 October | 22 | 0 | 22 |
| 2017 September | 16 | 0 | 16 |
| 2017 August | 18 | 0 | 18 |
| 2017 July | 25 | 2 | 27 |
| 2017 June | 21 | 9 | 30 |
| 2017 May | 28 | 11 | 39 |
| 2017 April | 30 | 15 | 45 |
| 2017 March | 13 | 21 | 34 |
| 2017 February | 8 | 15 | 23 |
| 2017 January | 8 | 2 | 10 |
| 2016 December | 29 | 24 | 53 |
| 2016 November | 0 | 13 | 13 |
| 2016 October | 0 | 12 | 12 |
| 2016 September | 3 | 11 | 14 |
| 2016 August | 8 | 1 | 9 |
| 2016 July | 3 | 0 | 3 |
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