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A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families
The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patien...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9563936/ https://www.ncbi.nlm.nih.gov/pubmed/36231115 http://dx.doi.org/10.3390/cells11193154 |
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author | Aldosary, Mazhor Alsagob, Maysoon AlQudairy, Hanan González-Álvarez, Ana C. Arold, Stefan T. Dababo, Mohammad Anas Alharbi, Omar A. Almass, Rawan AlBakheet, AlBandary AlSarar, Dalia Qari, Alya Al-Ansari, Mysoon M. Oláhová, Monika Al-Shahrani, Saif A. AlSayed, Moeenaldeen Colak, Dilek Taylor, Robert W. AlOwain, Mohammed Kaya, Namik |
author_facet | Aldosary, Mazhor Alsagob, Maysoon AlQudairy, Hanan González-Álvarez, Ana C. Arold, Stefan T. Dababo, Mohammad Anas Alharbi, Omar A. Almass, Rawan AlBakheet, AlBandary AlSarar, Dalia Qari, Alya Al-Ansari, Mysoon M. Oláhová, Monika Al-Shahrani, Saif A. AlSayed, Moeenaldeen Colak, Dilek Taylor, Robert W. AlOwain, Mohammed Kaya, Namik |
author_sort | Aldosary, Mazhor |
collection | PubMed |
description | The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant. |
format | Online Article Text |
id | pubmed-9563936 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95639362022-10-15 A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families Aldosary, Mazhor Alsagob, Maysoon AlQudairy, Hanan González-Álvarez, Ana C. Arold, Stefan T. Dababo, Mohammad Anas Alharbi, Omar A. Almass, Rawan AlBakheet, AlBandary AlSarar, Dalia Qari, Alya Al-Ansari, Mysoon M. Oláhová, Monika Al-Shahrani, Saif A. AlSayed, Moeenaldeen Colak, Dilek Taylor, Robert W. AlOwain, Mohammed Kaya, Namik Cells Article The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant. MDPI 2022-10-07 /pmc/articles/PMC9563936/ /pubmed/36231115 http://dx.doi.org/10.3390/cells11193154 Text en © 2022 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 | Article Aldosary, Mazhor Alsagob, Maysoon AlQudairy, Hanan González-Álvarez, Ana C. Arold, Stefan T. Dababo, Mohammad Anas Alharbi, Omar A. Almass, Rawan AlBakheet, AlBandary AlSarar, Dalia Qari, Alya Al-Ansari, Mysoon M. Oláhová, Monika Al-Shahrani, Saif A. AlSayed, Moeenaldeen Colak, Dilek Taylor, Robert W. AlOwain, Mohammed Kaya, Namik A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families |
title | A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families |
title_full | A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families |
title_fullStr | A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families |
title_full_unstemmed | A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families |
title_short | A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families |
title_sort | novel homozygous founder variant of rtn4ip1 in two consanguineous saudi families |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9563936/ https://www.ncbi.nlm.nih.gov/pubmed/36231115 http://dx.doi.org/10.3390/cells11193154 |
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