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First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria

Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis a...

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Autores principales: Belosevic, Adrian, Minder, Anna-Elisabeth, Gueuning, Morgan, van Breemen, Franziska, Thun, Gian Andri, Mattle-Greminger, Maja P., Meyer, Stefan, Baumer, Alessandra, Minder, Elisabeth I., Schneider-Yin, Xiaoye, Barman-Aksözen, Jasmin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533070/
https://www.ncbi.nlm.nih.gov/pubmed/37763293
http://dx.doi.org/10.3390/life13091889
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author Belosevic, Adrian
Minder, Anna-Elisabeth
Gueuning, Morgan
van Breemen, Franziska
Thun, Gian Andri
Mattle-Greminger, Maja P.
Meyer, Stefan
Baumer, Alessandra
Minder, Elisabeth I.
Schneider-Yin, Xiaoye
Barman-Aksözen, Jasmin
author_facet Belosevic, Adrian
Minder, Anna-Elisabeth
Gueuning, Morgan
van Breemen, Franziska
Thun, Gian Andri
Mattle-Greminger, Maja P.
Meyer, Stefan
Baumer, Alessandra
Minder, Elisabeth I.
Schneider-Yin, Xiaoye
Barman-Aksözen, Jasmin
author_sort Belosevic, Adrian
collection PubMed
description Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G>A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient’s blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics.
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spelling pubmed-105330702023-09-28 First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria Belosevic, Adrian Minder, Anna-Elisabeth Gueuning, Morgan van Breemen, Franziska Thun, Gian Andri Mattle-Greminger, Maja P. Meyer, Stefan Baumer, Alessandra Minder, Elisabeth I. Schneider-Yin, Xiaoye Barman-Aksözen, Jasmin Life (Basel) Communication Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G>A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient’s blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics. MDPI 2023-09-10 /pmc/articles/PMC10533070/ /pubmed/37763293 http://dx.doi.org/10.3390/life13091889 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Belosevic, Adrian
Minder, Anna-Elisabeth
Gueuning, Morgan
van Breemen, Franziska
Thun, Gian Andri
Mattle-Greminger, Maja P.
Meyer, Stefan
Baumer, Alessandra
Minder, Elisabeth I.
Schneider-Yin, Xiaoye
Barman-Aksözen, Jasmin
First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria
title First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria
title_full First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria
title_fullStr First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria
title_full_unstemmed First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria
title_short First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria
title_sort first report of a low-frequency mosaic mutation in the hydroxymethylbilane synthase gene causing acute intermittent porphyria
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533070/
https://www.ncbi.nlm.nih.gov/pubmed/37763293
http://dx.doi.org/10.3390/life13091889
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