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ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction

Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder due to pathogenic variants in the ITCH gene. It is characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity that can manifest variably with autoim...

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Autores principales: Wolfe, Rachel, Heiman, Paige, D'Annibale, Olivia, Karunanidhi, Anuradha, Powers, Alyssa, Mcguire, Marianne, Seminotti, Bianca, Dobrowolski, Steven F., Reyes-Múgica, Miguel, Torok, Kathryn S., Mohsen, Al-Walid, Vockley, Jerry, Ghaloul-Gonzalez, Lina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9634006/
https://www.ncbi.nlm.nih.gov/pubmed/36338154
http://dx.doi.org/10.1016/j.ymgmr.2022.100932
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author Wolfe, Rachel
Heiman, Paige
D'Annibale, Olivia
Karunanidhi, Anuradha
Powers, Alyssa
Mcguire, Marianne
Seminotti, Bianca
Dobrowolski, Steven F.
Reyes-Múgica, Miguel
Torok, Kathryn S.
Mohsen, Al-Walid
Vockley, Jerry
Ghaloul-Gonzalez, Lina
author_facet Wolfe, Rachel
Heiman, Paige
D'Annibale, Olivia
Karunanidhi, Anuradha
Powers, Alyssa
Mcguire, Marianne
Seminotti, Bianca
Dobrowolski, Steven F.
Reyes-Múgica, Miguel
Torok, Kathryn S.
Mohsen, Al-Walid
Vockley, Jerry
Ghaloul-Gonzalez, Lina
author_sort Wolfe, Rachel
collection PubMed
description Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder due to pathogenic variants in the ITCH gene. It is characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity that can manifest variably with autoimmune hepatitis, thyroiditis, and enteropathy, among other organ manifestations. It was originally described in 10 consanguineous Old Order Amish patients, and more recently in two patients of White British and Black German ethnicities. While the role of ITCH protein in apoptosis and inflammation has previously been characterized, a defect in cellular bioenergetics has not yet been reported in ITCH deficiency. Here we present a Caucasian female originally evaluated for possible mitochondrial respiratory chain deficiency, who ultimately was found to have two novel variants in ITCH with absence of ITCH protein in patient derived fibroblasts. Clinical studies of patient muscle showed mitochondrial DNA copy number of 57% compared to controls. Functional studies in skin fibroblasts revealed decreased activity of mitochondrial fatty acid oxidation and oxidative phosphorylation, and decreased overall ATP production. Our findings confirm mitochondrial energy dysfunction in a patient with ITCH deficiency offering the opportunity to assess alternative therapeutic options.
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spelling pubmed-96340062022-11-05 ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction Wolfe, Rachel Heiman, Paige D'Annibale, Olivia Karunanidhi, Anuradha Powers, Alyssa Mcguire, Marianne Seminotti, Bianca Dobrowolski, Steven F. Reyes-Múgica, Miguel Torok, Kathryn S. Mohsen, Al-Walid Vockley, Jerry Ghaloul-Gonzalez, Lina Mol Genet Metab Rep Research Paper Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder due to pathogenic variants in the ITCH gene. It is characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity that can manifest variably with autoimmune hepatitis, thyroiditis, and enteropathy, among other organ manifestations. It was originally described in 10 consanguineous Old Order Amish patients, and more recently in two patients of White British and Black German ethnicities. While the role of ITCH protein in apoptosis and inflammation has previously been characterized, a defect in cellular bioenergetics has not yet been reported in ITCH deficiency. Here we present a Caucasian female originally evaluated for possible mitochondrial respiratory chain deficiency, who ultimately was found to have two novel variants in ITCH with absence of ITCH protein in patient derived fibroblasts. Clinical studies of patient muscle showed mitochondrial DNA copy number of 57% compared to controls. Functional studies in skin fibroblasts revealed decreased activity of mitochondrial fatty acid oxidation and oxidative phosphorylation, and decreased overall ATP production. Our findings confirm mitochondrial energy dysfunction in a patient with ITCH deficiency offering the opportunity to assess alternative therapeutic options. Elsevier 2022-10-29 /pmc/articles/PMC9634006/ /pubmed/36338154 http://dx.doi.org/10.1016/j.ymgmr.2022.100932 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Wolfe, Rachel
Heiman, Paige
D'Annibale, Olivia
Karunanidhi, Anuradha
Powers, Alyssa
Mcguire, Marianne
Seminotti, Bianca
Dobrowolski, Steven F.
Reyes-Múgica, Miguel
Torok, Kathryn S.
Mohsen, Al-Walid
Vockley, Jerry
Ghaloul-Gonzalez, Lina
ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction
title ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction
title_full ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction
title_fullStr ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction
title_full_unstemmed ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction
title_short ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction
title_sort itch deficiency clinical phenotype expansion and mitochondrial dysfunction
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9634006/
https://www.ncbi.nlm.nih.gov/pubmed/36338154
http://dx.doi.org/10.1016/j.ymgmr.2022.100932
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