مقاله انگلیسی رایگان در مورد تقاطع ژنتیکی نوروفیلامنت-لیزوزومالی در شبکه قشری لکنت زبان – الزویر ۲۰۲۰

۱- Introduction

۲- Methods

۳- Results

۴- Discussion

References

Abstract

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG – a gene involved in the mannose-6-phosphate lysosomal targeting pathways – was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering.

Introduction

Persistent developmental stuttering is a speech disorder characterized by disruption in speech production fluency that has a typical but not exclusive onset during early childhood (2-4 years old) (Craig-MCQuaide et al. 2014; Yairi and Ambrose, 2013). The incidence and prevalence of stuttering varies according to age group (Craig et al. 2002; for a review please see Yairi and Ambrose, 2013). Lifetime incidence was estimated in 5% by Andrews and Harris (1964) but more recent investigations have given higher figures ranging from 5% to 18% (Mänsson, 2000; Felsenfeld et al. 2000; Craig et al. 2002; Dworzynski et al. 2007; Reilly et al. 2009). In the recent literature, prevalence has been summarized to be around 1% (Bloodstein and Ratner, 2008). In relation to prevalence, Yairi and Ambrose (2013) highlight how differences in prevalence are found depending on the age-group with figures ranging between 0.3% and 5.6% (Okalidou and Kampanaros, 2001; McLeod and Harrison, 2009; Proctor et al. 2008; McKinnon et al. 2007; van Borsel et al. 2006; Craig et al. 2002). There is a wide range in recovery rates reported, from 50% to 94% (Mänsson, 2000; Ryan, 2001; Craig et al. 2002; Mänsson, 2005; Dworzynski et al. 2007; Howell and Davis, 2011). Primary speech symptoms of stuttering include interruptions in normal fluency and time patterning of speech. Repeated occurrences of the following appear: sound and syllable repetitions, sound prolongations, interjections, broken words, silent blocking, circumlocutions, speech accompanied by physical tension and/or monosyllabic wholeword repetitions (American Psychiatric Association, 2013).