Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications

Kota Tamada,Keita Fukumoto,Tsuyoshi Toya,Fumihito Saitow,Hidenori Suzuki,Toru Takumi,Nobuhiro Nakai,Shinji Tanaka,François Spitz,Shigeo Okabe,Janak R Awasthi

doi:10.1038/s41467-021-24359-3

Abstract

Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.

Highlights

Inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD)
To test the functional significance of increased Snord[115], we generated the new mice with 1.5 Mb interstitial duplication in chromosome 7B (Fig. 1a and Supplementary Fig. 1), called the Prader–Willi syndrome (PWS)/Angelman syndrome (AS) locus, by using in vivo chromosome engineering[20,21]
The expected recombination was confirmed by conventional genomic PCR, Southern blot (Fig. 1b and Supplementary Fig. 1) and array comparative genomic hybridization (Fig. 1c)

Summary

Introduction

Inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). We conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An investigation found individuals with paternally derived duplication met the criteria for ASD, its penetrance was estimated at ~20% and the number of cases is still small[19] It remains unclear whether paternally expressed genes (PEGs) in 15q11-q13 contribute to the pathogenesis of ASD. We conducted rescue experiments by excluding the target gene from paternal 15q dup mice

Methods

Results

Conclusion