ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction.

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Immunology

Background:

• Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder caused by pathogenic variants in the ITCH gene.
• Clinical features include failure to thrive, facial dysmorphism, developmental delay, and variable systemic autoimmunity.
• Previous research focused on ITCH protein's role in apoptosis and inflammation, with no reported defects in cellular bioenergetics.

Purpose of the Study:

• To investigate potential mitochondrial dysfunction in a patient with ITCH deficiency.
• To identify novel variants in the ITCH gene and characterize their functional consequences.
• To explore the link between ITCH deficiency and cellular energy metabolism.

Main Methods:

• Genetic analysis to identify variants in the ITCH gene.
• Fibroblast culture and analysis of ITCH protein expression.
• Assessment of mitochondrial DNA copy number in patient muscle tissue.
• Functional assays in skin fibroblasts to evaluate mitochondrial fatty acid oxidation, oxidative phosphorylation, and ATP production.

Main Results:

• Two novel pathogenic variants in the ITCH gene were identified in the patient, leading to absence of ITCH protein in fibroblasts.
• Patient muscle showed a reduced mitochondrial DNA copy number (57% of controls).
• Fibroblast studies revealed decreased mitochondrial fatty acid oxidation, impaired oxidative phosphorylation, and reduced ATP production.

Conclusions:

• This study demonstrates mitochondrial energy dysfunction in a patient with ITCH deficiency.
• The findings highlight a previously unrecognized link between ITCH deficiency and cellular bioenergetic defects.
• This provides a basis for exploring novel therapeutic strategies targeting mitochondrial function in ADMFD.