A de novo germline mutation of KIT in a white‐spotted Brown Swiss cow

Abstract

SummaryWhite‐spotting coat colour phenotypes in cattle are either fixed characteristics of specific cattle breeds or occur sporadically owing to germline genetic variation of solid‐coloured parents. A Brown Swiss cow showing a piebald pattern resembling colour‐sidedness was referred for genetic evaluation. Both parents were normal solid‐brown‐coloured cattle. The cow was tested negative for the three known DNA variants in KIT, MITF and TWIST2 associated with different depigmentation phenotypes in Brown Swiss cattle. Whole‐genome sequencing of the cow was performed and a heterozygous variant affecting the coding sequence of the bovine KIT gene was identified on chromosome 6. The variant is a 40 bp deletion in exon 9, NM_001166484.1:c.1390_1429del, and leads to a frameshift that is predicted to produce a novel 50 amino acid‐long C‐terminus replacing almost 50% of the wt KIT protein, including the functionally important intracellular tyrosine kinase domain (NP_001159956.1:p.(Asn464AlafsTer50)). Interestingly, among three available offspring, two solid‐coloured daughters were genotyped as homozygous wt whereas a single son showing a slightly milder but still obvious depigmentation phenotype inherited a copy of the novel variant allele. The genetic findings provide strong evidence that the identified loss‐of‐function KIT variant most likely represents a de novo germline mutation that is causative owing to haploinsufficiency.

On-Target CRISPR/Cas9 Activity Can Cause Undesigned Large Deletion in Mouse Zygotes

“…As the first exon encodes only the 5 -UTR sequence and 22 out of the 979 amino acids (MRGARGAWDLLCVLLVLLRGQT) of the signal peptide, the generated deletion can be referred to as the Kit gene knockout. Several research groups have demonstrated that the white or white-spotting phenotype represents genetic mutations in the locus near and including the Kit gene (transmembrane tyrosine kinase receptor) in various organisms, such as alpacas [58], camels [59,60], cats [61], cows [62,63], dogs [64], donkeys [65], goats [66], horses [67], mice [68][69][70], pigs [71], rabbits [72], rats [73], yaks [74], humans [75,76], and even zebrafish [77]. The molecular mechanism behind this phenotype is linked to melanocyte migration and survival maintained by tyrosine-protein kinase KIT receptor.…”

Genetic Determination of the Amount of White Spotting: A Case Study in Siberian Cats

“…These results suggest that there are other factors involved that can affect the inheritance of the amount of white. Novel mutations within the KIT gene are still being discovered in other species such as cattle [ 4 ] or horses [ 6 ] and it’s possible that additional changes in a cat’s KIT gene are yet to be found. Other genes and interactions between them may be also involved [ 8 , 9 , 10 , 11 ].…”

“…White spots are present in many mammals such as horses, mice, cattle, dogs etc. [ 4 , 5 , 6 , 7 , 8 ]. In 1919, Whiting [ 9 ] mated cats and studied the inheritance of varying amounts of white-spotting.…”