A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder.

Zineb Ammous,Ethan Scott,Erik G Puffenberger,Emma L Baple,Andrew H Crosby,Lettie E Rawlins,Ryan M Ames,Joseph S Leslie,Barry A Chioza,Olivia Wenger,Lorna Harries,Rebecca Evans,Harold E Cross,Hannah Jones,Tom Herr,Angela Scheid,Joanna Kennedy,Jim Deline,Gregory M Cooper

doi:10.1371/journal.pgen.1009803

Abstract

SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-β signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.

Highlights

Smad proteins entail a family of structurally-related intracellular proteins that act as transcriptional regulators of the transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) pathway, crucially important for a variety of cellular processes including cell growth, differentiation and apoptosis [1]
Neurodevelopmental disorders are a group of conditions that may be inherited in families, characterized by impairments of the growth, development and function of the brain
These conditions may be associated with epilepsy, characterised by recurrent abnormal electrical activity in the brain

Summary

Introduction

Smad proteins entail a family of structurally-related intracellular proteins that act as transcriptional regulators of the transforming growth factor-beta (TGF-β)/bone morphogenetic protein (BMP) pathway, crucially important for a variety of cellular processes including cell growth, differentiation and apoptosis [1]. The Smad nuclear interacting protein 1 (SNIP1) gene encodes a widely expressed nuclear transcriptional regulator of several important molecular signalling pathways involved in embryogenesis. This evolutionarily conserved protein is made up of 396 amino acids, comprising a two-part nuclear localisation signal (NLS) and a forkhead-associated (FHA) domain (Fig 1H) [3,4]. The N-terminus NLS interacts with several Smads in the TGF-β signalling pathway [3], and inhibits the p65/RELA subunit of nuclear factor kappa-beta (NFkB; a primary transcription factor in proinflammatory signalling pathways) to act as a transcriptional repressor [4]. Genetic variants leading to disruption of the TGF-β/BMP molecular signalling pathway have been implicated in the pathogenesis of a number of inherited disorders, in particular connective tissue disorders associated with craniofacial (e.g. cleft palate and craniosynostosis), cardiovascular (e.g. aortic aneurysm and syndromic aortopathies), and musculoskeletal (e.g. disorders of endochondral ossification, bone growth, remodelling and limb development) outcomes [11]

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