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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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