A Link between Genetic Disorders and Cellular Impairment, Using Human Induced Pluripotent Stem Cells to Reveal the Functional Consequences of Copy Number Variations in the Central Nervous System-A Close Look at Chromosome 15.

Alessia Casamassa,Maurizio Gelati,Angelo Luigi Vescovi,Massimo Carella,Daniela Ferrari,Jessica Rosati

doi:10.3390/ijms21051860

Abstract

Recent cutting-edge human genetics technology has allowed us to identify copy number variations (CNVs) and has provided new insights for understanding causative mechanisms of human diseases. A growing number of studies show that CNVs could be associated with physiological mechanisms linked to evolutionary trigger, as well as to the pathogenesis of various diseases, including cancer, autoimmune disease and mental disorders such as autism spectrum disorders, schizophrenia, intellectual disabilities or attention-deficit/hyperactivity disorder. Their incomplete penetrance and variable expressivity make diagnosis difficult and hinder comprehension of the mechanistic bases of these disorders. Additional elements such as co-presence of other CNVs, genomic background and environmental factors are involved in determining the final phenotype associated with a CNV. Genetically engineered animal models are helpful tools for understanding the behavioral consequences of CNVs. However, the genetic background and the biology of these animal model systems have sometimes led to confusing results. New cellular models obtained through somatic cellular reprogramming technology that produce induced pluripotent stem cells (iPSCs) from human subjects are being used to explore the mechanisms involved in the pathogenic consequences of CNVs. Considering the vast quantity of CNVs found in the human genome, we intend to focus on reviewing the current literature on the use of iPSCs carrying CNVs on chromosome 15, highlighting advantages and limits of this system with respect to mouse model systems.

Highlights

The human genome, with its enormous structural complexity, goes through a rapid evolution due to structural variations (SV), which contribute to extend the genetic diversity among individuals and generations [1,2]
In order to narrow down this vast field of investigation, this review will focus solely on copy number variations (CNVs) located on chromosome 15 and associated diseases, with the aim of comparing the results derived from evaluation of mouse models with studies developed in induced pluripotent stem cells (iPSCs) and how the latter have transformed our perspectives and our prospects for understanding these syndromes
An increasing number of CNVs associated with disorders has been replicated in transgenic models; these systems have a questionable validity either by virtue of being non-human or because they are missing the genetic background typical of affected human subjects

Summary

Introduction

The human genome, with its enormous structural complexity, goes through a rapid evolution due to structural variations (SV), which contribute to extend the genetic diversity among individuals and generations [1,2]. In order to narrow down this vast field of investigation, this review will focus solely on CNVs located on chromosome 15 and associated diseases, with the aim of comparing the results derived from evaluation of mouse models with studies developed in iPSCs and how the latter have transformed our perspectives and our prospects for understanding these syndromes. The complexity of this region (chromosome 15) is highlighted on the one hand by the number of genotypes that have so far been characterized in patients and on the other hand, by the great variability of the correlated phenotypes. CYFIP1 interacts with fragile X mental retardation protein (FMRP) and with the Rho GTPase Rac and is involved in regulating axonal and dendritic outgrowth [75]

Within the BP2-BP3 Interval both Deletions and Duplications have been Mapped

CNVs between BP3 and BP4 are Rare

CNV Mouse Models

Induced Pluripotent Stem Cells for Modeling CNV

Findings

Conclusions