Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice

Abstract

Nesprin-2 is a nuclear envelope component and provides a link between cytoskeletal components of the cytoplasm and the nucleoplasm. Several isoforms are generated from its gene Syne2. Loss of the largest isoform Nesprin-2 Giant in mice is associated with a skin phenotype and altered wound healing, loss of C-terminal isoforms in mice leads to cardiomyopathies and neurological defects. Here we attempted to establish mice with an inducible knockout of all Nesprin-2 isoforms by inserting shRNA encoding sequences targeting the N- and C-terminus into the ROSA26 locus of mice. This caused early embryonic death of the animals harboring the mutant allele, which was presumably due to leaky expression of the shRNAs. Mutant embryos were only observed before E13. They had an altered appearance and were smaller in size than their wild type littermates. From this we conclude that the Nesprin-2 gene function is crucial during embryonic growth, differentiation and organogenesis.

<p>Implementation of Pharmacogenetics to Individualize Treatment Regimens for Children with Acute Lymphoblastic Leukemia</p>

“…67 Interestingly, variants of the SYNE2 have been linked to neurological diseases in mice. 68 In addition, the rs10513762 variant in mitochondrial ribosomal protein L47 (MRPL47) was shown by the same authors 66 to increase the risk of neurotoxicity. MRPL47 has also been shown to play a role in neurologic disorders.…”

Genetic basis of clinical variants of chemotherapy toxicity in children with acute lymphoblastic leukemia (literature review)

“…Первый полиморфизм -rs2781377 во втором белке ядерной оболочки, содержащем повторы спектрина (SYNE2), который кодирует несприн, белок, поддерживающий клеточный цитоскелет [57]. Интересно, что в экспериментальных работах на лабораторных животных, варианты SYNE2 были связаны с неврологическими заболеваниями у мышей [58]. Кроме того, вариант rs10513762 в гене митохондриального рибосомального белка L47 (MRPL47) повышает риск нейротоксичности [57].…”

“…Кроме того, вариант rs10513762 в гене митохондриального рибосомального белка L47 (MRPL47) повышает риск нейротоксичности [57]. В исследованиях in vitro было показано, что ген BAHD1 действует как регуляторный фактор воспаления и через эпигенетические механизмы способствует развитию вегетативных и сенсорных невропатий [58]. Эти полиморфизмы, изученные Abaji et al с помощью метода полногеномного секвенирования, были подтверждены в независимой репликационной когорте из 405 детей.…”

A Glance at the Nuclear Envelope Spectrin Repeat Protein 3

“…These results were unexpected, as no apparent disorders were observed, in total contrast to the cases involving the knockout of nesprin-1 or nesprin-2. Deletion of nesprin-1 or nesprin-2 can result in cardiomyopathy [40], and knockout of all nesprin-2 isoforms even caused early embryonic death [41]. To this surprising result, there are several possible explanations:…”