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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426922000921 |
| _version_ | 1811300269382696960 |
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| author | Rachel Wolfe Paige Heiman Olivia D'Annibale Anuradha Karunanidhi Alyssa Powers Marianne Mcguire Bianca Seminotti Steven F. Dobrowolski Miguel Reyes-Múgica Kathryn S. Torok Al-Walid Mohsen Jerry Vockley Lina Ghaloul-Gonzalez |
| author_facet | Rachel Wolfe Paige Heiman Olivia D'Annibale Anuradha Karunanidhi Alyssa Powers Marianne Mcguire Bianca Seminotti Steven F. Dobrowolski Miguel Reyes-Múgica Kathryn S. Torok Al-Walid Mohsen Jerry Vockley Lina Ghaloul-Gonzalez |
| author_sort | Rachel Wolfe |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T06:48:33Z |
| format | Article |
| id | doaj.art-9763ee3b6cd345f3adadf389b4604dbf |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-04-13T06:48:33Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-9763ee3b6cd345f3adadf389b4604dbf2022-12-22T02:57:29ZengElsevierMolecular Genetics and Metabolism Reports2214-42692022-12-0133100932ITCH deficiency clinical phenotype expansion and mitochondrial dysfunctionRachel Wolfe0Paige Heiman1Olivia D'Annibale2Anuradha Karunanidhi3Alyssa Powers4Marianne Mcguire5Bianca Seminotti6Steven F. Dobrowolski7Miguel Reyes-Múgica8Kathryn S. Torok9Al-Walid Mohsen10Jerry Vockley11Lina Ghaloul-Gonzalez12Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USAUPMC Clinical Genomics Laboratory, UPMC Magee-Womens Hospital, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USADivision of Clinical Chemistry, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USADivision of Clinical Chemistry, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USADivision of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USADivision of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author at: Division of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Rangos Research Building, Pittsburgh, PA 15224, USA.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.http://www.sciencedirect.com/science/article/pii/S2214426922000921ITCHAutoimmune diseaseUbiquitinationApoptosisE3 ligaseMitochondrial dysfunction |
| spellingShingle | Rachel Wolfe Paige Heiman Olivia D'Annibale Anuradha Karunanidhi Alyssa Powers Marianne Mcguire Bianca Seminotti Steven F. Dobrowolski Miguel Reyes-Múgica Kathryn S. Torok Al-Walid Mohsen Jerry Vockley Lina Ghaloul-Gonzalez ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction Molecular Genetics and Metabolism Reports ITCH Autoimmune disease Ubiquitination Apoptosis E3 ligase 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 | ITCH Autoimmune disease Ubiquitination Apoptosis E3 ligase Mitochondrial dysfunction |
| url | http://www.sciencedirect.com/science/article/pii/S2214426922000921 |
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