Genetic backgrounds and modifier genes of NTD mouse models: An opportunity for greater understanding of the multifactorial etiology of neural tube defects

Abstract

Neurulation, the early embryonic process of forming the presumptive brain and spinal cord, is highly complex and involves hundreds of genes in multiple genetic pathways. Mice have long served as a genetic model for studying human neurulation, and the resulting neural tube defects (NTDs) that arise when neurulation is disrupted. Because mice appear to show mostly single gene inheritance for NTDs and humans show multifactorial inheritance, mice sometimes have been characterized as a simpler model for the identification and study of NTD genes. But are they a simple model? When viewed on different genetic backgrounds, many genes show significant variation in the penetrance and expressivity of NTD phenotypes, suggesting the presence of modifier loci that interact with the target gene to affect the phenotypic expression. Looking at mutations on different genetic backgrounds provides us with an opportunity to explore these complex genetic interactions, which are likely to better emulate similar processes in human neurulation. Here, we review NTD genes known to show strain-specific phenotypic variation. We focus particularly on the gene Cecr2, which is studied using both a hypomorphic and a presumptive null mutation on two different backgrounds: one susceptible (BALB/c) and one resistant (FVB/N) to NTDs. This strain difference has led to a search for genetic modifiers within a region on murine chromosome 19. Understanding how genetic variants alter the phenotypic outcome in NTD mouse models will help to direct future studies in humans, particularly now that more genome wide sequencing approaches are being used. Birth Defects Research 109:140-152, 2017. © 2016 Wiley Periodicals, Inc.

A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect, anencephaly

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OligoPVP: Phenotype-driven analysis of individual genomic information to prioritize oligogenic disease variants

“…An alternative strategy for identification of candidate genes for highly heterogeneous human diseases is to use mouse genetics to identify phenotypic modifier genes. For example, neural tube defects are believed to involve more than 300 genes in the mouse, mutations in many of which need to be digenic or trigenic for expression of the phenotype 62 . Similarly, mouse double heterozygous mutants in Nkx2-1 and Pax8 show strain-specific thyroid dysgenesis phenotypes not seen in the individual mutations 63 .…”

OligoPVP: Phenotype-driven analysis of individual genomic information to prioritize oligogenic disease variants

“…An alternative strategy for identification of candidate genes for highly heterogeneous human diseases is to use mouse genetics to identify phenotypic modifier genes. For example, neural tube defects are believed to involve more than 300 genes in the mouse, mutations in many of which need to be digenic or trigenic for expression of the phenotype 36 . The scale of genetic interactions becoming apparent from mouse studies strongly supports the suggestion that in the human, we are only seeing the tip of a very important iceberg 37 .…”