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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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. |
format | Online Article Text |
id | pubmed-10533070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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