<i>SORBS2</i>is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

Ding, Yonghe; Yang, Jingchun; Chen, Peng; Lü, Tong; Jiao, Kunli; Tester, David J.; Jiang, Kai; Ackerman, Michael J.; Li, Yi‐Gang; Wang, Dao Wu; Wang, Dao Wen; Lee, Hon Chi; Xu, Xiaolei

doi:10.1101/725077

Cited by 2 publications

(3 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Deletion of Tbx1/10 or Dach causes ectopic FHF marker expression in SHF cells (57). Interestingly, a recent study has shown that SORBS2 mutation is associated with arrhythmogenic right ventricular cardiomyopathy (58), which is considered as a disease of disrupted differentiation of cardiac progenitor cells (59).…”

Section: Discussionmentioning

confidence: 99%

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Liang

Zhang

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

24Chromosome 4q deletion is one of the most frequently detected genomic imbalance events 25 in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions 26 do not include known CHD genes. Alignment of those 4q deletions defined a minimal 27 overlapping region including only one gene-SORBS2. Histological analysis of Sorbs2 -/heart 28 revealed atrial septal hypoplasia/aplasia or double atrial septum. Mechanistically, SORBS2 had 29 a dual role in maintaining sarcomeric integrity of cardiomyocytes and specifying the fate of 30 second heart field (SHF) progenitors through c-ABL/NOTCH/SHH axis. In a targeted 31 sequencing of a panel of known and candidate CHD genes on 300 CHD cases, we found that 32 rare SORBS2 variants were significantly enriched in CHD patients. Our findings indicate that 33 SORBS2 is a regulator of cardiac development and its haploinsufficiency may contribute to 34 cardiac phenotype of 4q deletion syndrome. The presence of double atrial septum in Sorbs2 -/-35 hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical 36 thromboembolism. 37 38 39 Keywords: 4q deletion syndrome, Congenital heart disease, SORBS2, second heart field, 40 Notch1 41 42 3 Introduction 43Congenital heart disease (CHD) is present in ~1% newborns (1). Although CHD is the most 44 common birth defect, the underlying causes of most CHDs remain elusive. Genetic 45 heterogeneity and gene-environment interaction limit the genotype-phenotype correlation and 46 complicate interpretation of CHD genetics. Anatomic rectification through interventional and 47 surgical treatments have greatly improved survival rate of CHD patients (2). However, the same 48 medical treatment often yields different outcomes in different CHD patients, suggesting the 49 underlying genetic lesion impacts CHD prognosis. Therefore, elucidation of CHD genetic basis 50 is becoming ever more important in both reducing short-term therapeutic complications and 51 improving long-term care of CHD patients. With the advances in genetic diagnosis techniques, 52 the discovery of genetic variants is no longer a limit (3). The interpretation of the association 53 of identified genetic variants with phenotype becomes the imperative need to address the 54 genetic basis of CHD. 55CNV is a chromosomal structural aberration comprising of deletion or duplication with a 56 size larger than 1kb. Due to the abundance of low-copy repeats and retrotransposons, CNVs 57 are quite common genetic variants in human genomes. Previous studies have estimated that 58 CNVs contribute to 10-15% CHD (4, 5). The most common chromosomal deletion is 59 Del22q11.2, which is the shared genetic cause of 3 clinical syndromes-DiGeorge syndrome, 60 velocardiofacial syndrome and conotruncal anomaly face syndrome (6). The common forms of 61 Del22q11.2 are ~3 or 1.5 Mbs deletion encompassing dozens of genes (6). The successful 62 identification of the major CHD gene TBX1 has greatly advanced our understanding of the 63 pathogenesis of 22q11.2 del...

show abstract

Section: Discussionmentioning

confidence: 99%

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Liang

Zhang

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, mutations in the RS domain prevent nuclear transport of RBM20 ( Murayama et al, 2018 ; Brodehl et al, 2019b ). Another ACM-associated gene encoding a putative RNA-binding protein ( Han et al, 2019 ) might be SORBS2 , encoding sorbin and SH3 domain-containing protein-2 ( Ding et al, 2019 ). The exact molecular function of SORBS2 is currently unknown.…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

“…However, in a preprinted manuscript, Ding et al described several novel human SORBS2 variants in ACM patients and generated cardiac-specific Sorbs2 -deficient mice. These mice develop biventricular cardiomyopathy, leading to an increased mortality ( Ding et al, 2019 ). However, it is currently unclear if SORBS2 is a RNA-binding protein or a desmosomal protein.…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

View full text Add to dashboard Cite

Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

show abstract

SORBS2is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

Cited by 2 publications

References 44 publications

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Contact Info

Product

Resources

About