WFS1関連の低周波難聴と共通マーモセットにおける代替スプライシングの同定

Approximately 200 genes have been identified as causative in hereditary hearing loss. Genetic testing is increasingly important-not only for accurate diagnosis but also for predicting audiometric profiles, prognoses, and potential syndromic features. Hereditary hearing loss can be syndromic or nonsyndromic, with nonsyndromic forms further classified by inheritance: autosomal-dominant or -recessive. In autosomal-dominant cases (ADNSHL), three pathological mechanisms-haploinsufficiency, dominant-negative effects and gain of function-are often implicated. Moreover, specific genes correlate with distinct audiometric patterns: WFS1 variants typically cause low-frequency hearing loss, whereas KCNQ4 and POU4F3 variants are linked to high-frequency loss. To investigate the underlying mechanisms of these frequency-dependent patterns, gene expression across cochlear turns was compared in mice-but interpretations of the results were limited because of inherent structural differences between rodent and primate cochleae. Therefore, the common marmoset (Callithrix jacchus), which offers closer anatomical and functional similarity to human cochleae, was utilized herein as an improved model. Using RNA sequencing (RNA-seq) across cochlear turns of common marmosets, the present study aimed to uncover gene expression and alternative splicing patterns that may explain tonotopic manifestations in hereditary hearing loss, including those caused by WFS1 variants-the present study being the such one using common marmoset cochlear RNA-seq data and these findings are highly valuable for genetic diagnosis and the development of gene therapies.