A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct...

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Neuroscience

Background:

• MCT8 deficiency, or Allan-Herndon-Dudley Syndrome, is a rare X-linked disorder caused by inactivating mutations in the MCT8 thyroid hormone transporter.
• Patients present severe neurological and endocrine issues with no effective treatments for neurological deficits.
• Developing a suitable mammalian model is crucial for investigating disease mechanisms and therapeutic strategies.

Purpose of the Study:

• To generate and characterize an avatar mouse model for MCT8 deficiency using CRISPR/Cas9 gene editing.
• To validate the P253L mutation's impact on thyroid hormone transport and disease phenotype.
• To establish a preclinical tool for evaluating potential therapies for neurological impairments.

Main Methods:

• CRISPR/Cas9 gene editing was employed to create a mouse model with a specific MCT8 mutation (P253L).
• In silico studies were conducted to predict the mutation's effect on the transporter's substrate binding pocket.
• Phenotypic characterization of the P253L mice included assessment of endocrine and neurological alterations.

Main Results:

• The P253L mouse model successfully recapitulated key endocrine alterations observed in MCT8 deficiency patients.
• Brain hypothyroidism and neurological deficits, including structural and functional changes, were identified in the P253L mice.
• The P253L mutation was predicted to impair thyroid hormone transport by altering the substrate binding pocket.

Conclusions:

• The P253L mouse is a valuable and accurate model for studying the pathophysiology of MCT8 deficiency.
• This model will facilitate the future testing of therapeutic interventions, such as gene therapy and pharmacological chaperones.
• The developed model holds promise for improving neurological outcomes in patients with Allan-Herndon-Dudley Syndrome.