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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | Life |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2075-1729/13/9/1889 |
| _version_ | 1827725537352613888 |
|---|---|
| author | Adrian Belosevic Anna-Elisabeth Minder Morgan Gueuning Franziska van Breemen Gian Andri Thun Maja P. Mattle-Greminger Stefan Meyer Alessandra Baumer Elisabeth I. Minder Xiaoye Schneider-Yin Jasmin Barman-Aksözen |
| author_facet | Adrian Belosevic Anna-Elisabeth Minder Morgan Gueuning Franziska van Breemen Gian Andri Thun Maja P. Mattle-Greminger Stefan Meyer Alessandra Baumer Elisabeth I. Minder Xiaoye Schneider-Yin Jasmin Barman-Aksözen |
| author_sort | Adrian Belosevic |
| collection | DOAJ |
| 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 <i>HMBS</i> 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 <i>HMBS</i> 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. |
| first_indexed | 2024-03-10T22:32:40Z |
| format | Article |
| id | doaj.art-1aa2f4fc9c104c9db505d8c902b9f107 |
| institution | Directory Open Access Journal |
| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-10T22:32:40Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Life |
| spelling | doaj.art-1aa2f4fc9c104c9db505d8c902b9f1072023-11-19T11:37:42ZengMDPI AGLife2075-17292023-09-01139188910.3390/life13091889First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent PorphyriaAdrian Belosevic0Anna-Elisabeth Minder1Morgan Gueuning2Franziska van Breemen3Gian Andri Thun4Maja P. Mattle-Greminger5Stefan Meyer6Alessandra Baumer7Elisabeth I. Minder8Xiaoye Schneider-Yin9Jasmin Barman-Aksözen10Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, SwitzerlandDivision of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Zürich, Triemli, 8063 Zurich, SwitzerlandDepartment of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, SwitzerlandInstitute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, SwitzerlandDepartment of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, SwitzerlandDepartment of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, SwitzerlandDepartment of Molecular Diagnostics and Cytometry, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, SwitzerlandInstitute of Medical Genetics, University of Zürich, 8952 Schlieren, SwitzerlandDivision of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Zürich, Triemli, 8063 Zurich, SwitzerlandInstitute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, SwitzerlandInstitute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, SwitzerlandAcute 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 <i>HMBS</i> 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 <i>HMBS</i> 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.https://www.mdpi.com/2075-1729/13/9/1889acute porphyriasacute intermittent porphyriade novo mutationmosaic mutationnanopore sequencing |
| spellingShingle | Adrian Belosevic Anna-Elisabeth Minder Morgan Gueuning Franziska van Breemen Gian Andri Thun Maja P. Mattle-Greminger Stefan Meyer Alessandra Baumer Elisabeth I. Minder Xiaoye Schneider-Yin Jasmin Barman-Aksözen First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria Life acute porphyrias acute intermittent porphyria de novo mutation mosaic mutation nanopore sequencing |
| 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 | acute porphyrias acute intermittent porphyria de novo mutation mosaic mutation nanopore sequencing |
| url | https://www.mdpi.com/2075-1729/13/9/1889 |
| work_keys_str_mv | AT adrianbelosevic firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT annaelisabethminder firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT morgangueuning firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT franziskavanbreemen firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT gianandrithun firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT majapmattlegreminger firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT stefanmeyer firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT alessandrabaumer firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT elisabethiminder firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT xiaoyeschneideryin firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria AT jasminbarmanaksozen firstreportofalowfrequencymosaicmutationinthehydroxymethylbilanesynthasegenecausingacuteintermittentporphyria |