Millwater Marissa, Bragg Camryn, Bishop Devin, Adeck Afuh, Karutury Rahul Chowdary, Weinhold Maximillian, Rao Praveen P N, Zhang Ruli, SheikhBahaei Shahriar
Neuron-Glia Signaling and Circuits Unit, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, 20892 MD, USA.
School of Pharmacy, Health Science Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1.
bioRxiv. 2025 Jul 31:2025.07.30.667752. doi: 10.1101/2025.07.30.667752.
Stuttering is a neurodevelopmental disorder characterized by involuntary disruptions in the normal fluency and timing of speech. Recently, stuttering has been related to specific point mutations in , a gene involved in lysosomal enzyme-targeting pathways, though it remains unclear how such a mutation might cause the stuttering phenotype. Herein, we studied mice engineered with the mutation in the gene found in humans who stutter and found increased iron deposition in the basal ganglia of these mice. Further, we found these iron deposits localized predominantly with regional astrocytes when Perls' stain was combined with an astrocyte-specific marker. Reducing iron deposition in the brain with iron chelation therapy improved vocalization symptoms in -mutant mice. Our data suggest a relationship between the mutation, iron homeostasis in astrocytes, and the stuttering phenotype, for which the underlying mechanisms remain to be elucidated.
口吃是一种神经发育障碍，其特征是正常言语流畅性和节奏出现非自愿性中断。最近，口吃与一个参与溶酶体酶靶向途径的基因中的特定点突变有关，不过尚不清楚这种突变如何导致口吃表型。在此，我们研究了携带在口吃人类中发现的该基因突变的工程小鼠，发现这些小鼠基底神经节中的铁沉积增加。此外，当用Perls染色法结合星形胶质细胞特异性标记物时，我们发现这些铁沉积物主要定位于局部星形胶质细胞。用铁螯合疗法减少大脑中的铁沉积可改善该基因突变小鼠的发声症状。我们的数据表明该基因突变、星形胶质细胞中的铁稳态与口吃表型之间存在关联，其潜在机制仍有待阐明。
