A heritable profile of six miRNAs in autistic patients and mouse models

Yusuf Ozkul,Serpil Taheri,Fatma Aybuga,Minoo Rassoulzadegan,Gokmen Zararsiz,François Cuzin,Arslan Bayram,Elif Funda Sener,Leila Kianmehr,Ecmel Mehmetbeyoglu,Didem Behice Öztop,Esra Tufan,Feyzullah Beyaz,Kezban Korkmaz Bayram,Nazan Dolu,Züleyha Doganyigit

doi:10.1038/s41598-020-65847-8

Abstract

Autism spectrum disorder (ASD) is a group of developmental pathologies that impair social communication and cause repetitive behaviors. The suggested roles of noncoding RNAs in pathology led us to perform a comparative analysis of the microRNAs expressed in the serum of human ASD patients. The analysis of a cohort of 45 children with ASD revealed that six microRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) were expressed at low to very low levels compared to those in healthy controls. A similar but less pronounced decrease was registered in the clinically unaffected parents of the sick children and in their siblings but never in any genetically unrelated control. Results consistent with these observations were obtained in the blood, hypothalamus and sperm of two of the established mouse models of ASD: valproic acid-treated animals and Cc2d1a+/− heterozygotes. In both instances, the same characteristic miRNA profile was evidenced in the affected individuals and inherited together with disease symptoms in the progeny of crosses with healthy animals. The consistent association of these genetic regulatory changes with the disease provides a starting point for evaluating the changes in the activity of the target genes and, thus, the underlying mechanism(s). From the applied societal and medical perspectives, once properly confirmed in large cohorts, these observations provide tools for the very early identification of affected children and progenitors.

Highlights

Autism spectrum disorder (ASD) is a group of developmental pathologies that impair social communication and cause repetitive behaviors
Among the miRNA genes in the mammalian genome, a large subset is expressed in the brain[8], and dysfunctions of particular miRNAs have been tentatively associated with neuropathological conditions, including ASD9,10, with diverging patterns of expression
The same pattern was observed in two mouse models, one generated via the injection of valproic acid (VPA), a drug known to induce autism in humans[11,12,13] and rodents[14,15] and another one resulting from heterozygosity of the Cc2d1a+/− locus, a gene of the ASD constellation encoding a transcriptional repressor of serotonin receptors[16,17]

Summary

Introduction

Autism spectrum disorder (ASD) is a group of developmental pathologies that impair social communication and cause repetitive behaviors. A similar but less pronounced decrease was registered in the clinically unaffected parents of the sick children and in their siblings but never in any genetically unrelated control Results consistent with these observations were obtained in the blood, hypothalamus and sperm of two of the established mouse models of ASD: valproic acid-treated animals and Cc2d1a+/− heterozygotes. In both instances, the same characteristic miRNA profile was evidenced in the affected individuals and inherited together with disease symptoms in the progeny of crosses with healthy animals. The same abnormal, disease-associated profile of expression of the same six microRNAs genes, in 45 patients, from multiplex (more than one child with autism) and simplex (one child with autism) families compared with their families and controls further extended to two of the established animal models

Methods

Results

Conclusion