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Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome
Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the i...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708263/ https://www.ncbi.nlm.nih.gov/pubmed/34948281 http://dx.doi.org/10.3390/ijms222413484 |
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author | Barbosa-Gouveia, Sofia Vázquez-Mosquera, Maria E. Gonzalez-Vioque, Emiliano Hermida-Ameijeiras, Álvaro Valverde, Laura L. Armstrong-Moron, Judith Fons-Estupiña, Maria del Carmen Wintjes, Liesbeth T. Kappen, Antonia Rodenburg, Richard J. Couce, Maria L. |
author_facet | Barbosa-Gouveia, Sofia Vázquez-Mosquera, Maria E. Gonzalez-Vioque, Emiliano Hermida-Ameijeiras, Álvaro Valverde, Laura L. Armstrong-Moron, Judith Fons-Estupiña, Maria del Carmen Wintjes, Liesbeth T. Kappen, Antonia Rodenburg, Richard J. Couce, Maria L. |
author_sort | Barbosa-Gouveia, Sofia |
collection | PubMed |
description | Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient’s DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient’s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant. |
format | Online Article Text |
id | pubmed-8708263 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87082632021-12-25 Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome Barbosa-Gouveia, Sofia Vázquez-Mosquera, Maria E. Gonzalez-Vioque, Emiliano Hermida-Ameijeiras, Álvaro Valverde, Laura L. Armstrong-Moron, Judith Fons-Estupiña, Maria del Carmen Wintjes, Liesbeth T. Kappen, Antonia Rodenburg, Richard J. Couce, Maria L. Int J Mol Sci Article Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient’s DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient’s fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant. MDPI 2021-12-15 /pmc/articles/PMC8708263/ /pubmed/34948281 http://dx.doi.org/10.3390/ijms222413484 Text en © 2021 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 Barbosa-Gouveia, Sofia Vázquez-Mosquera, Maria E. Gonzalez-Vioque, Emiliano Hermida-Ameijeiras, Álvaro Valverde, Laura L. Armstrong-Moron, Judith Fons-Estupiña, Maria del Carmen Wintjes, Liesbeth T. Kappen, Antonia Rodenburg, Richard J. Couce, Maria L. Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome |
title | Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome |
title_full | Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome |
title_fullStr | Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome |
title_full_unstemmed | Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome |
title_short | Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome |
title_sort | characterization of a novel splicing variant in acylglycerol kinase (agk) associated with fatal sengers syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708263/ https://www.ncbi.nlm.nih.gov/pubmed/34948281 http://dx.doi.org/10.3390/ijms222413484 |
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