Gene regulation analysis of patient-derived iPSCs and its CRISPR-corrected control provides a new tool for studying perturbations of ELMOD3 c.512A>G mutation during the development of inherited hearing loss

Abstract

The ELMOD3 gene is implicated in causing autosomal recessive/dominant non-syndromic hearing loss in humans. However, the etiology has yet to be completely elucidated. In this study, we generated a patient-derived iPSC line carrying ELMOD3 c.512A>G mutation. In addition, the patient-derived iPSC line was corrected by CRISPR/Cas9 genome editing system. Then we applied RNA sequencing profiling to compare the patient-derived iPSC line with different controls, respectively (the healthy sibling-derived iPSCs and the CRISPR/Cas9 corrected iPSCs). Functional enrichment and PPI network analysis revealed that differentially expressed genes (DEGs) were enriched in the gene ontology, such as sensory epithelial development, intermediate filament cytoskeleton organization, and the regulation of ion transmembrane transport. Our current work provided a new tool for studying how disruption of ELMOD3 mechanistically drives hearing loss.

Expanding Genotype/Phenotype Correlation in 2p11.2-p12 Microdeletion Syndrome

“…Based on the reported autosomal recessive inheritance in a consanguineous Pakistani family affected with non-syndromic deafness (DFNB88; OMIM #615429) [13], hearing loss was attributed to the homozygous deletion of ELMOD3 in this patient. Because hearing loss is not reported in the patients with a heterozygous deletion of ELMOD3, except for patient 3, the disease mechanism in a three-generation Chinese pedigree reported with ELMOD3-linked autosomal dominant non-syndromic deafness (DNFA81; OMIM #619500) may involve dominant-negative effects rather than haploinsufficiency [14][15][16]. Large ears are also reported in patient 8 [9], and a contribution to the external ear phenotype of one of three genes ELMOD3, CAPG and SH2D6 cannot be excluded.…”

The Inheritance of Hearing Loss and Deafness: A Historical Perspective

“…Genomic technologies have transformed medicine in the post-genome era, promising personalized and precise healthcare based on DNA sequencing. The existing literature on this subject is extensive, with numerous reports continuously emerging, presenting new discoveries for a better understanding of various alterations [82,83] and potential gene therapies [84].…”