Abstract
Congenital nystagmus (CN) is an ocular movement disorder manifested as involuntary conjugated binocular oscillation and usually occurs in early infancy. The pathological mechanism underlying CN is still poorly understood. We mapped a novel genetic locus 9q33.1-q34.2 in a larger Chinese family with autosomal dominant CN and identified a variant (c.47A>G/p.His16Arg) of STXBP1 by exome sequencing, which fully co-segregated with the nystagmus phenotype in this family and was absent in 571 healthy unrelated individuals. The STXBP1 encodes syntaxin binding protein 1 (also known as MUNC18-1), which plays a pivotal role in neurotransmitter release. In unc-18 (nematode homolog of MUNC18-1) null Caenorhabditis elegans, we found that the p.His16Arg exhibits a compromised ability to rescue the locomotion defect and aldicarb sensitivity, indicating a functional defect in neurotransmitter release. In addition, we also found an enhanced binding of the p.His16Arg mutant to syntaxin 3B, which is a homolog of syntaxin 1A and specifically located in retinal ribbon synapses. We hypothesize that the variant p.His16Arg of STXBP1 is likely to affect neurotransmitter release in the retina, which may be the underlying etiology of CN in this family. Our results provide a new perspective on understanding the molecular mechanism of CN.
Highlights
Congenital nystagmus (CN, OMIM 310700) is the involuntary oscillation of eyes, a common ocular disorder usually accompanied by reduced visual acuity, head nodding, strabismus and abnormal head position (Liu et al, 2007)
Pathogenic variants of STXBP1 have been associated with EIEE4, which is manifested as intractable epilepsy, severe developmental delay and mental retardation (Saitsu et al, 2008; Allen et al, 2016), while nystagmus was noted in a few cases (Stamberger et al, 2016)
Given the unc-18 null worms showing uncoordinated locomotion and strong resistance to aldicarb due to the severe synaptic transmission defects (Weimer et al, 2003), our findings that p.His16Arg could weaken the ability of MUNC18-1 to restore locomotion and sensibility to aldicarb of the unc-18 null worms suggests a compromised function of this mutant in neurotransmitter release, in particular the mutant might decrease acetylcholine release at neuromuscular junction of C. elegans (Figures 2A–I and Supplementary Figures S3A– G)
Summary
Congenital nystagmus (CN, OMIM 310700) is the involuntary oscillation of eyes, a common ocular disorder usually accompanied by reduced visual acuity, head nodding, strabismus and abnormal head position (Liu et al, 2007). It appears at birth or within the first few months of life, and often occurs in isolation or coupled with other visual diseases such as albinism, congenital cataracts, aniridia, or optic nerve hypoplasia (Gottlob and Proudlock, 2014). Identification of more pathogenic genes and further exploration of their physiological function will advance our understanding of the etiology and pathogenesis of nystagmus
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