A mouse model of Waardenburg syndrome type IV resulting from an ENU‐induced mutation in endothelin 3

Abstract

A line of mutant mice (114-CH19) exhibiting white spotting and preweaning lethality was identified during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. The trait segregated as a semidominant bellyspot with reduced penetrance. Homozygous mutant mice showed preweaning lethality, and exhibited white spotting over the majority of the body surface, with pigmented patches remaining around the pinnae, eyes and tail. Linkage analysis localized 114-CH19 on mouse chromosome 2, suggesting endothelin 3 (Edn3) as a candidate gene. Sequence analysis of Edn3 identified a G > A transversion that encodes an arginine to histidine substitution (R96H). This mutation is predicted to disrupt furin-mediated proteolytic cleavage of pro-endothelin that is necessary to form biologically active EDN3. This mutation is novel among human and mouse EDN3 mutants, is the first reported EDN3 ENU mutant, and is the second reported EDN3 point mutation. This study demonstrates the power of using ENU mutagenesis screens to generate new animal models of human disease, and expands the spectrum of EDN3 mutant alleles.

Review and update of mutations causing Waardenburg syndrome

“…This is compatible with the idea that the two NC-derived cell lineages require different minimal threshold levels of Ednrb expression Hosoda et al, 1994]. Since then, other mouse models have been generated [Druckenbrod et al, 2008;Matera et al, 2007;Matsushima et al, 2002;Shin et al, 1999]. Of note, the NC-specific excision of the receptor is sufficient to produce a WS4 phenotype.…”

Networks and pathways in pigmentation, health, and disease

“…[63][64][65][66][67][68][69] As mutations in some genes alone may cause embryonic lethality or may have melanocyte phenotypes too subtle to measure, screens have been established in mice with a known mutation that disrupts melanoblast homeostasis, thus sensitizing the animals to modest perturbations, but resulting in reproducible phenotypes. [70][71][72] While these approaches search for random loci that alter melanocyte function in the context of the whole animal, many aspects of melanocyte biology can be studied in melanocytes isolated away from the organism. Genome-wide approaches that knockdown gene expression in melanocyte cell culture have provided useful insights into function and disease, discovering new genes and cellular pathways functioning in melanocytes.…”

Life in the Fast Lane: Mammalian Disease Models in the Genomics Era

“…Implementation of forward genetics in mice, historically through N -ethyl- N -nitrosourea (ENU) mutagenesis (for review, see Kile and Hilton, 2005), has been effective not only in generating monoallelic mouse models of specific human diseases but also in identifying modifiers and genetic interactions through “sensitized” screens in models of diabetes, developmental neuropathies, and disorders such as Waardenburg's syndrome (Matera et al, 2007; Stottmann et al, 2011; Tchekneva et al, 2007). However, until recently, mapping disease-causative mutations following ENU treatment was notoriously time consuming and complex.…”