High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

Abstract

The 2019 International Skeletal Dysplasia Society nosology update lists 441 genes for which mutations result in rare human skeletal disorders. These genes code for enzymes (33%), scaffolding proteins (18%), signal transduction proteins (16%), transcription factors (14%), cilia proteins (8%), extracellular matrix proteins (5%), and membrane transporters (4%). Skeletal disorders include aggrecanopathies, channelopathies, ciliopathies, cohesinopathies, laminopathies, linkeropathies, lysosomal storage diseases, protein-folding and RNA splicing defects, and ribosomopathies. With the goal of evaluating the ability of mouse models to mimic these human genetic skeletal disorders, a PubMed literature search identified 260 genes for which mutant mice were examined for skeletal phenotypes. These mouse models included spontaneous and ENU-induced mutants, global and conditional gene knockouts, and transgenic mice with gene over-expression or specific base-pair substitutions. The human X-linked gene ARSE and small nuclear RNA U4ATAC, a component of the minor spliceosome, do not have mouse homologs. Mouse skeletal phenotypes mimicking human skeletal disorders were observed in 249 of the 260 genes (96%) for which comparisons are possible. A supplemental table in spreadsheet format provides PubMed weblinks to representative publications of mutant mouse skeletal phenotypes. Mutations in 11 mouse genes (Ccn6,

PHEXL222P Mutation Increases Phex Expression in a New ENU Mouse Model for XLH Disease

“…ENU mutagenesis is a particularly valuable methodology to recover an allelic series of point mutations for any gene enabling a more acute analysis of gene function [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. To date, 441 genes for which mutations result in rare human skeletal disorders are listed by the 2019 International Skeletal Dysplasia Society, from which 260 genes were examined for skeletal phenotypes using mutant mice and 37 phenotypes were successfully identified by ENU mouse mutagenesis [ 69 ]. Mutant mice generated by our ENU mutagenized screen present a short body size, hypophosphatemia with consistent hypocalcemia and an increased ALP plasma level.…”

Promoting validation and cross-phylogenetic integration in model organism research

“…The zebrafish system was established through primarily phenotype-first screens ( Amsterdam and Hopkins, 2006 ; Mullins et al, 2021 ), where in-depth biological analyses of genetic mutations predated molecular cloning. The Knockout Mouse Phenotyping Program (KOMP2) project provides a complementary, gene-first model for phenotyping practices ( Brommage and Ohlsson, 2019 ). The KOMP2 is the US component of the International Mouse Phenotyping Consortium (IMPC) that aims to knockout and functionally characterize all protein-coding genes in the mouse genome ( Cacheiro et al, 2019 ).…”

Knockout mice are an important tool for human monogenic heart disease studies

“…The standardised screens, which involve an ever-increasing number of wild-type mice, controlled for sex and other factors, are key for reproducibility. How well mouse models perform at mimicking disease phenotypes can be explored as a whole ( Cacheiro et al, 2019 ) or focusing on specific types of disorders ( Brommage and Ohlsson, 2019 ; McGraw et al, 2017 ). The IMPC is an evolving and frequently updated resource, with an increasing number of mouse knockouts and corresponding phenotype data points captured by data releases that provide stable and versioned reference sets of analysed data.…”