[en] Sifrim-Hitz-Weiss syndrome (SIHIWES) is a rare neurodevelopmental disorder primarily caused by mutations in the CHD4 gene. This syndrome presents a range of congenital anomalies and dysmorphic features affecting various organs, including the brain, heart, and inner ear.
This study investigated the role of the chromodomain helicase DNA-binding protein 4 (CHD4), an ATP-dependent chromatin remodeler and a key component of the nucleosome remodeling and deacetylase (NuRD) complex, in human inner ear development. Utilizing human embryonic stem cell (hESC)-derived cochlear organoids as an experimental model, this research explored the effects of a patient-specific missense mutation (CHD4 p.Gly1003Asp), linked to Sifrim-Hitz-Weiss syndrome (SIHIWES), as well as a haploinsufficient CHD4 knockout (CHD4KO/+). The study revealed that both genetic alterations led to significant disruptions in cochlear organoid development. Characterized by an increase in organoid size, enhanced proliferation of PAX2+ otic progenitors, and elevated levels of apoptosis.
RNA sequencing of the PAX2+ otic progenitors derived from the mutant organoids demonstrated the dysregulation of several developmental pathways, notably WNT and Notch signaling. Furthermore, the analysis unveiled alterations in chromatin accessibility, particularly an increased accessibility of neurogenic and non-otic transcription factors, as well as increase in accessibility at the transforming growth factor beta 1 (TGFB1) promoter, a gene not typically activated during inner ear differentiation. These findings underscore the critical role of CHD4 in regulating cell proliferation, apoptosis, and the differentiation of otic progenitors during human inner ear development. Disruptions in CHD4 function contribute to the complex developmental abnormalities observed in SIHIWES patients, potentially by impairing the balance between neurogenic and inner ear differentiation programs. This research sheds light on the molecular underpinnings of SIHIWES and illustrates the value of using human inner ear organoids to investigate the inner ear development and associated disorders.
