Generation and mutational analysis of a transgenic murine model of the human MAF mutation

Aymé‐Gripp syndrome is an autosomal dominant multisystem disorder. The major clinical features of this syndrome include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. MAF has been identified as a causative gene of the syndrome, an...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2023-07, Vol.191 (7), p.1878-1888
Main Authors: Fujino, Mitsunori, Ojima, Masami, Ishibashi, Shun, Mizuno, Seiya, Takahashi, Satoru
Format: Article
Language:English
Subjects:
Animal models
Aymé‐Gripp syndrome
Cataracts
CRISPR
CRISPR‐Cas9
Genome editing
Genotyping
Glycogen
Glycogen synthase kinase 3
Growth rate
GSK3‐mediated MAF disorders
Hearing loss
Hereditary diseases
Intellectual disabilities
Kinases
Maf
Mutation
Phenotypes
Phosphorylation
transcription factors
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Summary:Aymé‐Gripp syndrome is an autosomal dominant multisystem disorder. The major clinical features of this syndrome include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. MAF has been identified as a causative gene of the syndrome, and heterozygous variants owing to impairment in glycogen synthase kinase 3 (GSK3)‐mediated MAF phosphorylation shows related disorders. However, the underlying mechanisms of these types of disorders in affected individuals remain poorly understood. To explore the underlying mechanisms and discover new phenotypes, a murine model with a Maf mutation on a GSK3 phosphorylation motif, p.Thr58Ile, was generated using CRISPR‐Cas9 gene editing. This is a homologous mutation to that in human patients. Our murine model exhibited similar phenotypes to those in humans, such as lens abnormalities, short stature, growth retardation, and abnormal skull morphology. The murine model showed decreased brain volume and malocclusion. Considering the sequencing and genotyping data, our models were successfully generated for the first time (to the best of our knowledge). Therefore, this study offers new and unique functional insights into human and murine MAF and novel clinical values of MAF pathogenic variants associated with changes in the functions of several organs based on a viable murine model.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.63220