A MITF Mutation Associated with a Dominant White Phenotype and Bilateral Deafness in German Fleckvieh Cattle

Bettina Lupp,Veronika Stein,Andrea Tipold,Ottmar Distl,Stefanie Mömke,Jürgen Rehage,Johanna Corinna Eule,Xiuhcun (Cindy) Tian,Ute Philipp

doi:10.1371/journal.pone.0028857

Abstract

A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). This syndrome has been mapped to bovine chromosome (BTA) 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF) as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans.

Highlights

A German Fleckvieh cattle family has been ascertained segregating for a white coat phenotype
Identification of the associated mutation Among 13 genes contained in the associated interval on BTA22 of Btau 4.0/5.2 (Ensemble, http://www.ensembl.org/index.html), we considered the microphthalmia-associated transcription factor (MITF) gene at 32,353,746–32,387,234 bp as the most plausible candidate
In German White Fleckvieh, a perfect cosegregation was demonstrated for a missense mutation affecting the DNA binding domain of MITF

Summary

Introduction

A German Fleckvieh cattle family has been ascertained segregating for a white coat phenotype. Examination of these animals revealed a phenotype similar to incomplete albinism. The German White Fleckvieh represents the first reported dominant white cattle with heterochromia irides and bilateral hearing loss. White coat color and heterochromia irides are often associated with congenital sensorineural deafness [4]. Phenotypes similar to these dominant white cattle are known in humans as Waardenburg Syndrome Type 2A (WS2A) [5] and Tietz syndrome (TS) [6,7,8]. The objectives of this study were to characterize the phenotypes of German White Fleckvieh and to identify the mutation responsible for this newly detected phenotype in cattle using genome-wide association analyses and re-sequencing of MITF, the most likely candidate gene

Objectives

Methods

Results

Conclusion